1,3,6-trihydro-6-aza-3-oxapentalen-2-one derivatives for the treatment of neoplasia

ABSTRACT

1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One Derivatives of Formula I are useful for inducing or promoting apoptosis and for arresting uncontrolled neoplastic cell proliferation, and are specifically useful in the arresting and treatment of neoplasia: ##STR1## Wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, lower alkyl, and benzyl, 
     R 3  and R 4  are selected from the group consisting of substituted or unsubstituted phenyl, and the like, 
     R 5  is selected from the group consisting of hydrogen, lower alkyl, and the like, 
     Y is selected from the group consisting of CH 2 , C═O, CH--OH; m is an integer from 0-3; X is selected from the group consisting of CH 2 , C═O, CH--OH, and SO 2  ; and n is an integer from 0-2.

This application is a divisional of U.S. application Ser. No. 09/174,815filed Oct. 19, 1998, which is incorporated herein by reference, now U.S.Pat. No. 5,939,417.

TECHNICAL FIELD

This invention relates to compounds and methods for inducing orpromoting apoptosis and for arresting uncontrolled neoplastic cellproliferation, methods that are specifically useful in the arresting andtreatment of neoplasias, including precancerous and cancerous lesions.

BACKGROUND OF THE INVENTION

Pharmaceuticals that are effective against early stage neoplasiascomprise an emerging and expanding area of research and potentialcommercial development. Such pharmaceuticals can delay or arrestdevelopment of precancerous lesions into cancers. Each year in theUnited States alone, untold numbers of people develop precancerouslesions, which exhibit a strong statistically significant tendency todevelop into malignant tumors, or cancer. Such lesions include lesionsof the breast (that can develop into breast cancer), lesions of the skin(that can develop into malignant melanoma or basal cell carcinoma),colonic adenomatous polyps (that can develop into colon cancer),cervical dysplasia (cervical cancer) and other such neoplasms.

Such compounds and methods are particularly beneficial tosub-populations of patients who repeatedly develop precancerous lesions,and therefore have a statistically higher probability of getting cancer.Many cancer types (e.g., breast, colon, prostate etc.) have such patientsub-populations.

The search for drugs useful for treating and preventing neoplasias intheir earliest stages is intensive because chemotherapy and surgery oncancer itself is often not effective, and current cancer chemotherapyhas severe side effects. Such cancer-preventative compounds are alsoenvisaged for recovered cancer patients who retain a risk of cancerreoccurrence, and even for cancer patients who would benefit fromcompounds that selectively induce apoptosis in neoplastic, butsubstantially not in normal cells.

Because it is believed that chronic administration ofcancer-preventative pharmaceuticals is necessary to inhibit or arrestthe development of neoplasia, standard cancer chemotherapeutic drugs arenot considered appropriate drugs for cancer chemoprevention becausewhatever cancer preventative (as opposed to cancer-fighting)capabilities those drugs may possess do not outweigh their severe sideeffects. Most standard chemotherapeutics are now believed to kill cancercells by inducing apoptosis (also sometimes referred to as "programmedcell death"). Apoptosis naturally occurs in many tissues in the body.Apoptosis plays a critical role in tissue homeostasis, that is, itensures that the number of new cells produced are correspondingly offsetby an equal number of cells that die. Apoptosis is especially pronouncedin self-renewing tissues such as bone marrow, immune cells, gut, andskin. For example, the cells in the intestinal lining divide so rapidlythat the body must eliminate cells after only three days to protect andprevent the overgrowth of the intestinal lining.

Standard chemotherapeutics promote apoptosis not only in cancer cells,but also in normal human tissues, and therefore have a particularlysevere effect on tissues where apoptosis is especially pronounced (e.g.hair, gut and skin). The results of those effects include hair loss,weight loss, vomiting and bone marrow immune suppression. Thus, standardchemotherapeutics are inappropriate for cancer prevention, particularlyif chronic administration is indicated.

Several non-steroidal anti-inflammatory drugs ("NSAIDs"), originallydeveloped to treat arthritis, have shown effectiveness in inhibiting andeliminating colonic polyps. Polyps virtually disappear when the patientstake the drug, particularly when the NSAID sulindac is administered.However, the continued prophylactic use of currently available NSAIDs,even in high colon cancer-risk patients, is still marked by severe sidereactions that include gastrointestinal irritations, perforations,ulcerations and kidney toxicity believed to be produced by inhibition ofprostaglandin synthetase activity ("PGE-2"). Such inhibition is arequirement for the NSAIDs anti-inflammatory action since elevatedlevels of PGE-2 are associated with inflammation. PGE-2 plays aprotective function in the gastrointestinal tract, which is the reasonsuch gastric side effects arise with chronic NSAID therapy, which israrely indicated for arthritis sufferers, acute therapy being the normfor them. However, chronic administration of sulindac is important forhigh cancer-risk patients to eliminate and prevent future polyps whichcause gastric side effects in many such patients. Once NSAID treatmentis terminated due to such complications, the neoplasms return,particularly in high risk patients.

Compounds such as those disclosed in U.S. Pat. No. 5,643,959 haveexhibited advantages in the treatment of neoplastic lesions since suchcompounds have been shown to induce apoptosis in neoplastic cells butnot in normal cells in humans (see Piazza et al. Gastroenterology Vol.112, A629, 1997). Thus, the severe side effects due to induction ofapoptosis in normal cells by conventional chemotherapeutics are avoidedby these novel therapeutics (see, Piazza et al. Cancer Research Vol. 57,pp. 2452-2459, 1997). In addition, such compounds do not exhibit thegastric side effects associated with NSAIDs since such compounds do notsubstantially inhibit PGE-2. More potent compounds with such neoplasiaspecificity but without substantial PGE-2 activity are desirable.

SUMMARY OF THE INVENTION

This invention represents potent compounds that inhibit the growth ofneoplastic cells, for treating patients with neoplastic lesions. Thisinvention also involves methods for inducing such specific inhibition ofneoplastic cells by exposing such cells to a pharmacologically effectiveamount of those compounds described below to a patient in need of suchtreatment. Such compositions are effective in modulating the growth ofneoplasms.

DETAILED DESCRIPTION OF THE INVENTION

As discussed above, the present invention includes compounds of FormulaI below (as well as their pharmaceutically acceptable salts) fortreating a patient with neoplastic, particularly precancerous, andcancerous lesions: ##STR2## wherein R₁ and R₂ are independently selectedfrom the group consisting of hydrogen, lower alkyl, and benzyl;

R₃ is selected from the group consisting of substituted or unsubstitutedphenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, imidazolidinyl, piperidinyl, pyrazinyl,piperazinyl, pyrimidinyl, tetrazolyl, morpholinyl, triazinyl, furfuryl,and thiophenyl, and lower alkyl, wherein said substitutents are one tothree independently selected from the group consisting of halogen, loweralkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino,hydroxy, nitro, nitrile, carboxyl, aminosulfonyl, lower alkyl mercapto,and lower alkylsulfonyl;

R₄ is selected from the group consisting of substituted or unsubstitutedphenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, imidazolidinyl, piperidinyl, pyrazinyl,piperazinyl, pyrimidinyl, tetrazolyl, morpholinyl, triazinyl, furfuryl,thiophenyl, and lower alkyl; wherein said substitutents are one to threeindependently selected from the group consisting of halogen, loweralkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino,hydroxy, nitro, nitrile, carboxyl, aminosulfonyl, lower alkyl mercapto,and lower alkylsulfonyl;

R₅ is selected from the group consisting of hydrogen, lower alkyl,halogen, hydroxy, amino, lower alkyl amino, and dilower alkylamino;

Y is selected from the group consisting of CH₂, C═O, CH--OH

m is an integer from 0-3

X is selected from the group consisting of CH₂, C═O, CH--OH, and SO₂ ;and

n is an integer from 0-2.

Preferred compounds of this invention include those where

R₁ and R₂ are independently selected from the group consisting ofhydrogen and lower alkyl;

R₃ is selected from the group consisting of substituted or unsubstitutedphenyl, pyridinyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl,pyrimidinyl, triazinyl, furfuryl, thiophenyl, and lower alkyl, whereinsaid substituents are one to three independently selected from the groupconsisting of lower alkyl, lower alkoxy, amino, lower alkylamino, anddi-lower alkylamino, carboxyl, aminosulfonyl and alkylsulfonyl.

R₄ is selected from the group consisting of substituted or unsubstitutedphenyl, pyridinyl, pyrroyl, imidazolidinyl, pyrazinyl, piperazinyl,pyrimidinyl, morpholinyl, triazinyl, thiophenyl, and lower alkyl,wherein said substituents are one to three independently selected fromthe group consisting of lower alkoxy, amino, di-lower-alkylamino,hydroxy, nitrile, carboxyl, aminosulfonyl and alkylsulfonyl;

R₅ is selected from the group consisting of hydrogen, lower alkyl,hydroxy and diloweralkylamino;

Y is selected from the group consisting of CH--OH and C═O;

m is an integer from 0-2;

X is selected from the group consisting of CH₂, C═O and SO₂ ; and

n is either 0 or 1

More preferred compounds of this invention include those wherein

R₁ and R₂ are both lower alkyl;

R₃ is selected from the group consisting of phenyl, pyridinyl,pyrazinyl, pyrimidinyl, and triazinyl, wherein said substituents are oneto three independently selected from the group consisting of loweralkyl, lower alkoxy, di-lower-alkylamino, aminosulfonyl and alkylsulfonyl;

R₄ is selected from the group consisting of substituted or unsubstitutedphenyl, pyridinyl, pyrazinyl, pyrimidinyl, morpholinyl, triazinyl,thiophenyl, and lower alkyl, wherein said substituents are one to threeindependently selected from the group consisting of lower alkoxy,di-lower-alkylamino, aminosulfonyl and alkylsulfonyl;

R₅ is selected from the group consisting of hydrogen and lower alkyl;

Y is C═O;

M is 0 or 1;

X is CH₂ ; and

n=0

The present invention is also a method of treating individuals withneoplastic lesions by administering a pharmacologically effective amountof an enterically coated pharmaceutical composition that includescompounds of this invention.

Preferably, such compounds are administered without therapeutic amountsof an NSAID.

Also, the present invention is a method of inhibiting the growth ofneoplastic cells by exposing the cells to an effective amount ofcompounds of Formula I

As used herein, the term "precancerous lesion" includes syndromesrepresented by abnormal neoplastic, including dysplastic, changes oftissue. Examples include dysplasic growths in colonic, breast, bladderor lung tissues, or conditions such as dysplastic nevus syndrome, aprecursor to malignant melanoma of the skin. Examples also include, inaddition to dysplastic nevus syndromes, polyposis syndromes, colonicpolyps, precancerous lesions of the cervix (i.e., cervical dysplasia),esophagus, prostatic dysplasia, bronchial dysplasia, breast, bladderand/or skin and related conditions (e.g., actinic keratosis), whetherthe lesions are clinically identifiable or not.

As used herein, the term "cancerous" refers to lesions that aremalignant. Examples include malignant melanomas, breast cancer, prostatecancer and colon cancer.

As used herein, the term "neoplasm" refers to both precancerous andcancerous lesions and hyperplasia.

As used herein, the term "halo" or "halogen" refers to chloro, bromo,fluoro and iodo groups, and the term "alkyl" refers to straight,branched or cyclic alkyl groups and to substituted aryl alkyl groups.The term "lower alkyl" refers to C₁ to C₈ alkyl groups.

The term "lower alkoxy" refers to alkoxy groups having from 1 to 8carbons, including straight, branched or cyclic arrangements.

The term "lower alkylmercapto" refers to a sulfide group that issubstituted with a lower alkyl group; and the term "lower alkylsulfonyl" refers to a sulfone group that is substituted with a loweralkyl group.

The term "pharmaceutically acceptable salt" refers to non-toxic acidaddition salts and alkaline earth metal salts of the compounds ofFormula I. The salts can be prepared in situ during the final isolationand purification of such compounds, or separately by reacting the freebase or acid functions with a suitable organic acid or base, forexample. Representative acid addition salts include the hydrochloride,hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmetate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,mesylate, citrate, maleate, fumarate, succinate, tartrate,glucoheptonate, lactobionate, lauryl sulfate salts and the like.Representative alkali and alkaline earth metal salts include the sodium,calcium, potassium and magnesium salts.

It will be appreciated that certain compounds of Formula I can possessan asymmetric carbon atom and are thus capable of existing asenantiomers. Unless otherwise specified, this invention includes suchenantiomers, including any racemates. The separate enantiomers may besynthesized from chiral starting materials, or the racemates can beresolved by conventional procedures that are well known in the art ofchemistry such as chiral chromatography, fractional cyrstallization ofdiastereomeric salts and the like.

Compounds of this invention may be formulated into pharmaceuticalcompositions together with pharmaceutically acceptable carriers for oraladministration in solid or liquid form, or for intraveneous, rectal ortopical administration, although carriers for oral administration aremost preferred.

Pharmaceutically acceptable carriers for oral administration includecapsules, tablets, pills, powders, troches and granules. In such soliddosage forms, the carrier can comprise at least one inert diluent suchas sucrose, lactose or starch. Such carriers can also comprise, as isnormal practice, additional substances other than diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, troches and pills, the carriers may also comprise bufferingagents. Carriers such as tablets, pills and granules can be preparedwith enteric coatings on the surfaces of the tablets, pills or granules.Alternatively, the enterically coated compound can be pressed into atablet, pill, or granule, and the tablet, pill or granules foradministration to the patient. Preferred enteric coatings include thosethat dissolve or disintegrate at colonic pH such as shellac or EudragetS.

Pharmaceutically acceptable carriers include liquid dosage forms fororal administration, e.g., pharmaceutically acceptable emulsions,solutions, suspensions, syrups and elixirs containing inert diluentscommonly used in the art, such as water. Besides such inert diluents,compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring andperfuming agents.

Pharmaceutically acceptable carriers for topical administration includeDMSO, alcohol or propylene glycol and the like that can be employed withpatches or other liquid-retaining material to hold the medicament inplace on the skin so that the medicament will not dry out.

Pharmaceutically acceptable carriers for rectal administration arepreferably suppositories that may contain, in addition to the compoundsof this invention excipients such as cocoa butter or a suppository wax,or gel.

The pharmaceutically acceptable carrier and compounds of this inventionare formulated into unit dosage forms for administration to a patient.The dosage levels of active ingredient (i.e., compounds of thisinvention) in the unit dosage may be varied so as to obtain an amount ofactive ingredient effective to achieve lesion-eliminating activity inaccordance with the desired method of administration (i.e., oral orrectal). The selected dosage level therefore depends upon the nature ofthe active compound administered, the route of administration, thedesired duration of treatment, and other factors. If desired, the unitdosage may be such that the daily requirement of the active compound isin one dose, or divided among multiple doses for administration, e.g.,two to four times per day.

The pharmaceutical compositions of this invention are preferablypackaged in a container (e.g., a box or bottle, or both) with suitableprinted material (e.g., a package insert) containing indications,directions for use, etc.

The general scheme for producing compounds useful in this invention isillustrated and explained below. ##STR3##

Scheme I describes the general procedure which leads to compounds ofFormula I. An appropriate chloromethyl lower alkylketone (R₅ --C(O)--CH₂--Cl) is added to a mixture of an appropriate di-loweralkylacetonedicarboxylate, preferably the diethylester (EtO₂ C--CH₂ --C(O)--C(R₁,R₂)--CO₂ Et) and a lower alkylamine (R₄ --NH₂), preferably in an aqueousmedium. The reaction temperature is preferably maintained just below 60°C., and after a few hours, the mixture is treated with ice-hydrochloricacid (reaction 1). The thus obtained ring-closed pyrrole (a) is acylatedwith an acyl halide under Friedel-Crafts reaction conditions to give thepyrrole-ester (c) (reaction 3). The 5-acyl product (c) is subjected to ahydrolysis with moderately concentrated alkali (e.g., NaOH) to yield thefree di-acid (d) (reaction 4), which is partly reesterified with anacidic solution of ethanol to give the 5-acyl-3-carboxy-pyrrole-esterderivative (e) (reaction 5). Decarboxylation of the carboxy group in3-position is accomplished by heating (e) in a suitable organic solvent(reaction 6) to yield the alkyl 5-acyl-pyrrole-ester-derivative (f),which is hydrolysed (e.g., with NaOH) to give the free acid (i)(reaction 10). The pyrrole acid derivative (i) is subjected toN-bromosuccunimide to yield the lactone (j) (reaction 11).

In an alternative way to achieve the lactone (j), the acyl rest in5-position is added at a later stage. Starting with the pyrrolederivative (a), hydrolysis in the usual manner (e.g., with NaOH; see,reaction 2) gives the dicarboxylic acid (b). Partial reesterificationwith an acidic solution of ethanol yields the 3-carboxy-pyrrole-esterderivative (g) (reaction 7), which is decarboxylated in the 3-positionby heating it in a suitable solvent (e.g., quinoline) (reaction 9). Theresulting pyrrole-ester (h) is subjected to a Friedel Crafts reactionwith an acylhalide to yield the 5-acyl-pyrrole-ester derivative (f),which is converted to the lactone (j), as described above (see reactions10 and 11). ##STR4##

Scheme II is employed when R₄ is hydrogen. A substituted oxime and asubstituted ethylacetonedicarboxylate are allowed to react according toa Knorr pyrrole synthesis in glacial acetic acid and zinc dust to yieldthe ring closed pyrrole (k) (reaction 12). Hydrolysis of the diester (k)with a moderately concentrated alkali (e.g., NaOH) gives the freedicarboxylic acid (l) (reaction 13), which is re-esterified with anacidic ethanol solution (reaction 14) to yield the ethyl5-acyl-3-carboxy pyrrole ester derivative (m). Decarboxylation of thecarboxy group in 3-position is accomplished by heating the ester (m) inan organic solvent (e.g., quinoline) (reaction 15) to give thepyrrole-ester (n), which is hydrolysed in the usual manner (e.g., withNaOH) to yield the free acid (o) (reaction 16). After protecting thesecondary amine by reaction with t-butyloxycarbonyl-anhydride (reaction17), the lactone (q) is formed by reaction with N-bromosuccinimide(reaction 18). The BOC-group is removed with trifluoroacetic acid,followed by a mild basic workup (e.g., NaHCO₃) to yield the lactone (r)(reaction 19).

Scheme III is employed if R₄ is a group which is sensitive towardsFriedel Crafts conditions, (i.e., Reactions 9 or 3 in Scheme I). Thelactone (r) in a basic solution is allowed to react with analkylhalide(R₄ --(X)_(n) -Hal), acylhalide or sulfonylhalide to give theN-substituted lactone (s) (reaction 20), which can be reduced withsodium borohydride to the lactone (t) with a secondary alcohol inposition 5 (reaction 21).

Scheme IV is employed if a nitrile, i.e.,1-methyl-pyrrole-2-acetonitrile, is available as a starting material forreaction 22, which is a Friedel Crafts acylation with R₃ --C(O)--Cl andAlCl₃ as reagents. The nitrile (u) is hydrolysed with base (reaction 23)to give the acid (v). The lactone (s) is formed by reaction withN-bromosuccinimide (reaction 24).

To summarize, the reagents and conditions for Scheme I-III are asfollows (numbers refer to reactions):

1. aqueous solution, <60° C.; H⁺

2. A) NaOH (25-50%)

B) HCl

3. Friedel-Crafts reaction with R₃ --C(O)--Cl

4. A) NaOH (25-50%)

B) HCl

5. EtOH, H⁺

6. Δ, quinoline, --CO₂ ↑

7. EtOH, H⁺ (Other lower alkylalcohols can be employed instead ofethanol.)

8. Δ, quinoline, --CO₂ ↑

9. Friedel-Crafts reaction with R₃ --C(O)--Cl

10. A) NaOH (25-50%)

B) HCl

11. N-bromosuccinimide

12. Knorr pyrrole synthesis conditions: Zn/CH₃ COOH

13. A) NaOH (25-50%)

B) HCl

14. EtOH, H⁺ (Other lower alkylalcohols can be employed instead ofethanol)

15. Δ, quinoline, --CO₂ ↑

16. A) NaOH (25-50%);

B) HCl

17. (BOC)₂ O

18. N-bromosuccinimide

19. A) CF₃ COOH/CH₂ Cl₂

B) base

20. R₄ --(X)_(n) -Hal

21. NaBH₄

22. Friedel-Crafts reaction with R₃ --C(O)--Cl

23. 1N NaOH reflux

24. N-Bromosuccinimide

The following examples are intended to illustrate, but not to limit, thescope of the present invention.

EXAMPLE 16-Methyl-5-(p-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Toluoyl)-1-methylpyrrole-2-acetonitrile

To a cooled suspension of 26.6 g. (0.2 mole) aluminum chloride in 80 ml.dichloroethane is added dropwise 30.8 g. (0.2 mole) p-toluoyl chloride.The resulting solution is added dropwise to a solution of1-methylpyrrole-2-acetonitrile in 80 ml. dichloroethane cooledexternally with an ice bath. After the addition, the resulting solutionis stirred at room temperature for twenty minutes and then refluxed forthree minutes. The solution is poured into ice acidified with dilutehydrochloric acid. The organic and aqueous fractions are separated. Theaqueous fraction is extracted once with chloroform. The organicfractions are combined and washed successively withN,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid, saturatedsodium bicarbonate solution and saturated sodium chloride solution. Theorganic fraction is dried over anhydrous magnesium sulfate. The solventis then evaporated off. Upon trituration of the residue with methanol, asolid crystallizes, 5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, whichis removed by filtration and purified by recrystallization from benzene.Additional product is isolated from the mother liquors which arecombined, concentrated in vacuo, and the resulting oily residue columnchromatographed on neutral alumina using hexane, benzene and ether assuccessive solvents. The product is isolated by concentrating in vacuothe first few major compound-bearing fractions (10% ether in benzene).The solids are combined and recrystallized from methanol and then frombenzene-hexane, m.p. 102-105° C.

(B) 5-(p-Toluoyl)-1-methylpyrrole-2-acetic acid

A solution of 3.67 g. (0.015 mole) of5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, 24 ml. of 1N sodiumhydroxide, and 50 ml. of 95% ethanol is stirred and refluxed fortwenty-four hours. The resulting solution is poured into ice acidifiedwith dilute hydrochloride acid. A white solid precipitates which isextracted into ether. The ether phase is washed with a saturatedsolution of sodium chloride and dried over anhydrous magnesium sulfate.The solvent is evaporated and a white solid,5-(p-toluoyl)-1-methylpyrrole-2-acetic acid, is obtained which isrecrystallized twice from isopropanol, m.p. 155-157° C.

(C) 6-Methyl-5-(p-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

N-bromosuccinimide (0.94 g, 5.2 mmol) is added stepwise at 0° C. to astirred solution of 5-(p-toluoyl)-1-methylpyrrole-2-acetic acid (0.70 g,2.39 mmol) in DMA/water (6 ml, 0.1 ml). After 30 minutes at 0° C.,stirring is continued overnight at room temperature. The solution isadded dropwise to stirred ice water (150 ml). A white precipitate isfiltered off, is washed with water (2×10 ml), and is dried in vacuo.Recrystallization from methylene chloride-n-hexane gives a white solid,6-methyl-5-(p-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one, withm.p. 148-151° C. (R₁ =H, R₂ =H, R₃ =4-methylphenyl, R₄ =CH₃, R₅ =H,Y=CO, m=1, n=0). Formula: C₁₅ H₁₃ NO₃ ; Molecular Mass: 255.27 g/mol; ¹H-NMR [ppm] (CDCl₃): 2.43 (s,3,Ph-CH₃); 3.85 (s,2,--CH₂ --C═O); 3.97(s,3,N--CH₃); 6.71 (s,1,═CH--); 7.25-7.72 (AB, 4,ar.); IR [cm⁻¹ ] (KBr):1740 C═O; 1630 C═C.

EXAMPLE 26-Methyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate

To a solution of (22.0 g. (0.131 mole) of ethylN-methylpyrrole-2-acetate and 24.5 g. (0.14 mole) of p-chlorobenzoylchloride in 120 ml. of carbon disulfide is added 35.0 g. (0.262 mole) ofanhydrous aluminum chloride over a period of 20 minutes withintermittant cooling to keep the temperature at 25° C. The mixture isstirred for an additional 20 minutes. The carbon disulfide solvent isthen decanted and discarded. The red gummy residue is washed with hexaneand dilute hydrochloric acid and ice is added to the mixture. Themixture is extracted with ether. The ether solution is shaken with anaqueous solution of dimethylaminopropylamine and washed with dilutehydrochloric acid followed by brine. The solution is dried overmagnesium sulfate and treated with charcoal. After removal of thecharcoal, the solvent is evaporated in vacuo leaving a partiallycrystalline red oil as a residue. This material is extracted with three500 ml. portions of boiling pentane. The combined pentane extracts areevaporated in vacuo, and the residue is crystallized from 60 ml. of coldmethanol. The resulting solid is collected and washed with coldmethanol; there is obtained about 6.3 g of a white crystalline solid,ethyl 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate, m.p. 74-76° C.Recrystallization from methyl cyclohexane raises the melting point to78-80° C.

(B) 5-(p-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid

A suspension of 3.06 g. (0.01 mole) ofethyl-5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate in 25 ml. of 0.5 Nsodium hydroxide is refluxed for 30 minutes. About two-thirds of thissolution is cooled, washed with ether, and then acidified with dilutehydrochloric acid. The resulting solid precipitate is collected byfiltration, dried and recrystallized from ethanol-water to give theproduct, 5-(p-chlorobenzoyl)-1-metylpyrrole-2-acetic acid; m.p. 189-191°C. Upon recrystallization from ethanol-water, the melting point is188-190° C. Analysis: Calcd. for C₁₄ H₁₂ ClNO₃ : C, 60.54; H, 4.36; N,5.05%. Found: C, 60.54; H, 4.37; N, 5.14%.

(C)6-Methyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =p-chlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 36-Methyl-5-(3'4'-Dibromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(3'4'-dibromobenzoyl)-1-methyl-pyrrole-2-acetate and5-benzoyl-1-methyl-pyrrole-2-acetic acid

By following the procedure of Example 2, part A, except that anequivalent quantity of 3'4'dibromobenzoyl chloride is employed in placeof the p-chlorobenzoylchloride used in Example 2, ethyl5-(3'4'-dibromobenzoyl)-1-methyl-pyrrole-2-acetate is produced; and5-(3'4'-dibromobenzoyl)-1-methyl-pyrrole-2-acetic acid is produced whenthe procedure of Example 2, part B is employed.

(B)6-Methyl-5-(3'4'-dibromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one5-(3',4')-Dibromobenzoyl-1-methyl-pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce6-methyl-5-(3'4'-dibromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3'4'-dibromobenzoyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 4 6-Methyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-Benzoyl-1-methylpyrrole-2-acetonitrile

To a chilled suspension of 9.7 g. (0.07 mole) of aluminum chloride in 45ml. methylene chloride is added 9 ml. (0.07 mole) benzoyl chloride. Theresulting solution is added dropwise to a solution of1-methylpyrrole-2-acetonitrile in 30 ml. methylene chloride whilecooling externally with an ammonium chloride ice bath (temperature below5° C.). After the addition is complete, the reaction mixture is stirredat 0° C. for fifteen minutes and then poured into ice acidified with 3Nhydrochloric acid. The acidic fraction is extracted three times withmethylene chloride. The organic fractions are combined and washedconsecutively with N,N-dimethyl-1,3-propanediamine and 3N hydrochloricacid. The organic solution is dried over anhydrous magnesium sulfate.The solvent is then evaporated off to yield an oily residue which iscolumn chromatographed on neutral alumina using hexane, benzene andethylacetate as successive solvents. The first few fractions havingultraviolet absorption in the 240-260 mμ range contain the desiredproduct. These fractions are combined, the solvent evaporated off, andthe oily residue, when triturated with methanol, yields the crystallineproduct, 5-benzoyl-1-methylpyrrole-2-acetonitrile, m.p. 106-108° C.

(B) 5-Benzoyl-1-methylpyrrole-2-acetic acid:

A suspension of 2.42 g. (0.11 mole) of5-benzoyl-1-methylpyrrole-2-acetonitrile, 0.9 g. (0.22 mole) sodiumhydroxide, 6 ml. water, and 0.5 ml. ethanol, is stirred and refluxed forone hour. The resulting solution is cooled and extracted in water andchloroform. The aqueous fraction is made acidic with 3N hydrochloricacid. A white solid, 5-benzoyl-1-methylpyrrole-2-acetic acid,precipitates which is filtered and washed with a hexane-ether solution,m.p. 144-145° C. Analysis: Calcd. for C₁₄ H₁₃ NO₃ : C, 69.12; H, 5.39;N, 5.76%. Found: C, 69.23; H, 5.47; N, 5.78%.

(C) 6-Methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-Benzoyl-1-methylpyrrole-2-acetic acid is subjected to the procedure ofExample 1, part C to produce6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H, R₂=H, R₃ =phenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 56-Methyl-5-(m-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(m-Chlorobenzoyl)-1-methylpyrrole-2-acetonitrile

To a cooled suspension of 16.6 g. (0.12 mole) aluminum chloride in 60ml. 1,2-dichloroethane is added dropwise 23 g. (0.12 mole)m-chlorobenzoylchloride. The resulting suspension is added dropwise to acooled solution of 15 g. (0.12 mole) 1-methylpyrrole-2-acetonitrile in60 ml. 1,2-dichloroethane. The reaction mixture is stirred for abouttwenty minutes at room temperature and then heated and refluxed forthree minutes. The reaction is terminated by pouring the mixture intoice acidified with 3N hyrochloric acid. The resulting two fractions areseparated. The aqueous fraction is washed with chloroform. The organicfractions are combined and washed consecutively withN,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturatedsodium chloride solution. The organic fraction is then dried overanhydrous magnesium sulfate. The solvent is evaporated, and theresulting residue is triturated with cold methanol to yield aprecipitate of the desired product which is filtered off and set aside.The methanol filtrate is concentrated in vacuo, and the remaining oilyresidue is chromatographed on a column packed with neutral alumina usinghexane, benzene and ether as the successive solvents. The desiredproduct is isolated by evaporation of the first few compound-bearing(ether) fractions. The solids are combined and recrystallized frommethanol to yield 5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile,m.p. 122-127° C.

Analysis: Calcd. for C₁₄ H₁₁ ClN₂ O: N, 10.83%. Found: N, 10.52

(B) 5-(m-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid

A mixture of 2.8 g. (0.01 mole) of5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, 22 ml. of 1N sodiumhydroxide solution and 5 ml. ethanol is stirred at reflux for 15 hours.Some of the ethanol is evaporated. The remaining solution is poured intoice acidified with dilute hydrochloric acid. A white solid,5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetic acid, precipitates which isrecrystallized twice from methanol: water, m.p. 165° C.

Analysis: Calcd. for C₁₄ H₁₂ ClNO₃ : C, 60.54; H, 4.36; N, 5.05%. Found:C, 60.61; H, 4.40; N, 4.87%.

(C)6-Methyl-5-(m-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(m-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-Methyl-5-(m-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =m-chlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 66-Methyl-5-(p-Bromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-bromobenzoyl)-1-methylpyrrole-2-acetonitrile

The procedure of Example 5 is repeated except that an equivalentquantity of p-bromobenzoyl chloride is used in place of them-chlorobenzoyl chloride used therein to yield,5-(p-bromobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p. 139-141° C.

(B) 5-(p-Bromobenzoyl)-1-methylpyrrole-2-acetic acid

By following the procedure of Example 5B, using an equivalent quantityof the nitrile from part A in place of the5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile used therein5-(p-bromobenzoyl)-1-methylpyrrole-2-acetic acid, m.p. 188° C. isobtained.

(C) 6-Methyl-5-(p-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Bromobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(p-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁=H, R₂ =H, R₃ =p-bromophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 76-Methyl-5-(p-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Fluorobenzoyl)-1-methylpyrrole-2-acetonitrile

The procedure of Example 5A is repeated except that an equivalentquantity of p-fluorobenzoyl chloride is used in place of them-chlorobenzoyl chloride used therein to yield5-(p-fluorobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p. 134-136° C.

(B) 5-(p-Fluorobenzoyl)-1-methylpyrrole-2-acetic acid

By following the procedure of Example 5B, using an equivalent quantityof the nitrile from part A in place of the5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile used therein,5-(p-fluorobenzoyl)-1-methylpyrrole-2-acetic acid, m.p. 164-165° C. isobtained.

(C)6-Methyl-5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Fluorobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =p-fluorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 86-Methyl-5-(o-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(o-Chlorobenzoyl)-1-methylpyrrole-2-acetonitrile

To a cooled suspension of 14 g. (0.105 mole) aluminum chloride in 45 ml.dichloroethane is added dropwise, 18.5 g. (0.105 mole) o-chlorobenzoylchloride. The resulting solution is added dropwise to a cooled (0° C.)solution of 1-methylpyrrole-2-acetonitrile in 45 ml. dichloroethanekeeping the temperature at approximately 10° C. The mixture is stirredat room temperature for about twenty minutes, and then refluxed forthree minutes. It is poured into ice acidified with 3N hydrochloricacid, and the resulting two layers are separated. The aqueous fractionis extracted twice with chloroform. The organic fractions are combinedand washed twice with N,N-dimethyl-1,3-propanediamine, once with 3Nhydrochloric acid and once with saturated sodium chloride solution. Theorganic fraction is dried over anhydrous magnesium sulfate. The solventis evaporated, and the resulting oil is chromatographed on a columnpacked with neutral alumina using benzene and ether as successivesolvents. The first compound-bearing fractions contain the desiredproduct. The solvent is evaporated and the resulting oil crystallizesupon treatment with methanol. The solid product,5-(o-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is purified byrecrystallization from benzene:cyclohexane solution, m.p. 80-85° C.

(B) 5-(o-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid

A solution of 2.4 g. (0.009 mole) of5-(o-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, 18 ml. of 1N sodiumhydroxide and 18 ml. 95% ethanol is stirred and refluxed for sevenhours. The ethanol is evaporated off, and the remaining solid residue isdissolved in water and washed with chloroform. The aqueous layer is madeacidic with 3N hydrochloric acid. An oil precipitates which crystallizeswhen scratched. The solid is filtered and washed with water and hexane.The solid is purified by recrystallization from methanol:water and againfrom ether:hexane, m.p. 140-141° C. Analysis: Calcd. for C₁₄ H₁₂ ClNO₃₁: C, 60.54; H, 4.36; N, 5.05%. Found: C, 60.55; H, 4.43; N, 4.91%.

(C)6-Methyl-5-(o-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(o-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-Methyl-5-(o-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =o-chlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m-1, n=0).

EXAMPLE 96-Methyl-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(2',4'-Dichlorobenzoyl)-1-methylpyrrole-2-acetonitrile

To a suspension of 16.6 g. (0.125 mole) of aluminum chloride in 60 ml.1,2-dichloroethane is added 26.2 g. (0.125 mole) of 2,4-dichlorobenzoylchloride. The resulting solution is added slowly to a solution of 15 g.(0.125 mole) of 1-methylpyrrole-2-acetonitrile in 60 ml.1,2-dichloroethane while cooling externally with an ice bath. After theaddition is complete, the mixture is stirred for 40 minutes at roomtemperature followed by heating at reflux for 3 minutes. It is thenpoured into ice acidified with dilute hydrochloric acid. The organicphase is separated and washed successively withN,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid, and saturatedsodium chloride solution. It is then dried over magnesium sulfate andthe solvent evaporated. The resulting red oily residue ischromatographed on a column packed with neutral alumina and eluted withbenzene and ether. The first compound-bearing fractions upon evaporationyield a white solid,5-(2',4'-dichlorobenzoyl)-1-methylpyrrole-2-acetonitrile, which ispurified by recrystallization from methanol, m.p. 129-130° C. Analysis:Calcd. for C₁₄ H₁₀ Cl₂ N₂ O: N, 9.56%. Found: N, 9.51%.

(B) 5-(2',4'-Dichlorobenzoyl)-1-methylpyrrole-2-acetic acid

A solution of 4.3 g. (0.015 mole) of5-(2',4'-dichlorobenzoyl)-1-methylpyrrole-2-acetonitrile in 30 ml. 1Nsodium hydroxide and 30 ml. 95% ethanol is refluxed overnight. Thesolution is concentrated and poured into dilute hydrochloric acid. Awhite solid, 5-(2',4'-dichlorobenzoyl)-1-methylpyrrole-2-acetic acidprecipitates which is recrystallized from iso-propanol and methanol,m.p. 165-166° C. Analysis: Calcd. for C₁₄ H₁₁ Cl₂ NO₃ : C, 53.86; H,3.55; N, 4.68%. Found: C, 53.97; H, 3.66; N, 4.69%.

(C)6-Methyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2',4'-Dichlorobenzoyl)-1-methylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce6-methyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =2',4'-dichlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 106-Methyl-5-(o-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One6-Methyl-5-(m-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One6-Methyl-5-(p-Ethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One6-Methyl-5-(3',4'-Dimethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) By repeating the procedure of Example 8A, except that an equivalentquantity of o-toluoyl chloride, m-toluoyl chloride, p-ethylbenzoylchloride and 3,4-dimethylbenzoyl chloride is used in lieu of the2,4-dichlorobenzoyl chloride used therein, there are obtained asrespective products the corresponding 5-(o-toluoyl), 5-(m-toluoyl),5-(p-ethylbenzoyl) and 5-(3',4'-dimethylbenzoyl) derivatives of1-methylpyrrole-2-acetonitrile.

(B) The procedure of Example 8B is repeated, using an equivalentquantity of each of the foregoing nitrites in place of the5-(2',4'-dichlorobenzoyl)-1-methylpyrrole-2-acetonitrile used therein,to yield the products identified above, which are the corresponding5-(o-toluoyl), 5-(m-toluoyl), 5-(p-ethylbenzoyl) and5-(3',4'-dimethylbenzoyl) derivatives of 1-methylpyrrole-2-acetic acid.

(C) The 5-(o-toluoyl), 5-(m-toluoyl), 5-(p-ethylbenzoyl) and5-(3',4'-dimethylbenzoyl) derivatives of 1-methylpyrrole-2-acetic acidfrom part B are each separately subjected to the procedure of Example 1,part C to produce6-methyl-5-(o-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one,6-methyl-5-(m-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one,6-methyl-5-(p-ethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one,and6-methyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one,respectively.

EXAMPLE 116-Methyl-5-(p-Anisoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Methyl 5-(p-anisoyl)-1-methylpyrrole-2-acetate

A solution of 17.0 g. (0.1 mole) of p-anisoyl chloride and 13.3 g. (0.1mole) of aluminum chloride in 200 ml. of methylene chloride is addedover 5 minutes to a solution of methyl 1-methylpyrrole-2-acetate in 100ml. of methylene chloride at ice bath temperature. The mixture isstirred for 25 minutes and poured into ice acidified with dilutehydrochloric acid. The organic layer is separated and the aqueous layeris washed with methylene chloride. The combined organic solutions arewashed successively with dimethylaminopropylamine solution, dilutehydrochloric acid and brine and then dried over anhydrous magnesiumsulfate. The solvent is evaporated in vacuo to give a dark oily residuewhich is crystallized from 40 ml. of cold methanol. The solid iscollected by filtration, washed with cold methanol and recrystallizedfrom methanol to give white crystalline methyl5-(p-anisoyl)-1-methylpyrrole-2-acetate, m.p. 104-105° C.

(B) 5-(p-Anisoyl)-1-methylpyrrole-2-acetic acid

A solution of 3.00 g. (0.0105 mole) of methyl5-(p-anisoyl)-1-methylpyrrole-2-acetate in 12 ml. (0.012 mole) of 1Nsodium hydroxide solution and 5 ml. of 95% ethanol is refluxed for 30minutes. The solution is diluted with water, and the ethanol isevaporated in vacuo. The solution is filtered, and the filtrateacidified with dilute hydrochloric acid. The precipitated solid iscollected by filtration, dried and recrystallized from methanol-water togive white 5-(p-anisoyl)-1-methylpyrrole-2-acetic acid, m.p. 170-171° C.Analysis: Calcd. for C₁₅ H₁₅ NO₄ : C, 65.92; H, 5.53; N, 5.13%. Found:C, 66.01; H, 5.62; N, 5.12%

(C) 6-Methyl-5-(p-anisoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Anisoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(p-anisoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H,R₂ =H, R₃ =4'-methoxyphenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 126-Methyl-5-(m-Anisoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One6-Methyl-5-(-Ethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

By repeating the procedures of Examples 11A and 11B successively, exceptthat an equivalent quantity each of m-anisoyl chloride andp-ethoxybenzoyl chloride is initially employed in place of p-anisoylchloride, there are obtaine d as ester products, the corresponding5-(m-anisoyl) and 5-(p-ethoxybenzoyl) derivatives of methyl1-methylpyrrole-2-acetate, and as acid products, the above-captionedcorresponding 5-(m-anisoyl) and 5-(p-ethoxybenzoyl) derivatives of1-methylpyrrole-2-acetic acid, respectively. The acids are converted tothe corresponding lactones following the procedure of Example 1, part C(R₁ =H, R₂ =H, R₃ =3'-methoxyphenyl or 4'-ethoxyphenyl, R₄ =CH₃, R₅ =H,Y=CO, m=1, n=0).

EXAMPLE 136-Methyl-5-(3'-Chloro-4'-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(3'Chloro-p-toluoyl)-1-methylpyrrole-2-acetonitrile

21.4 grams (0.114 mole) of 3-chloro-4-methylbenzoylchloride is added toa suspension of 15.2 g. (0.114 mole) aluminum chloride in 50 ml.1,2-dichloroethane. The resulting solution is added dropwise to achilled solution of 13.7 g. (0.114 mole) of1-methylpyrrole-2-acetonitrile in 50 ml. 1,2-dichloroethane. After theaddition is complete, the mixture is stirred for ten minutes at roomtemperature, and then heated to reflux for three minutes. It is pouredinto ice acidified with dilute HCl. The organic phase is separated andwashed consecutively with N,N-dimethyl-1,3-propanediamine, 3Nhydrochloric acid and saturated sodium chloride solution. It is thendried over anhydrous magnesium sulfate, and the solvent evaporated off.A white solid, 5-(3'-chloro-p-toluoyl)-1-methyl pyrrole-2-acetonitrile,precipitates from the resulting oily residue upon trituration withmethanol which is purified by recrystallization from methanol, m.p.116-118° C. Analysis: Calcd. for C₁₅ H₁₃ ClN₂ O: N, 10.26%. Found: N,10.38%.

(B) 5-(3'-Chloro-p-toluoyl)-1-methylpyrrole-2-acetic acid

A solution of 3.5 g. (0.0013 mole) of5-(3'-chloro-p-toluoyl)-1-methylpyrrole-2-acetonitrile in 18 ml. 95%ethanol and 26 ml. 1N sodium hydroxide is heated at reflux overnight.The reaction mixture is then cooled and poured into dilute hydrochloricacid. The resulting white precipitate,5-(3'-chloro-p-toluoyl)-1-methylpyrrole-2-acetic acid, is filtered offand purified by recrystallization once from isopropanol, m.p. 176-178°C.

(C)6-Methyl-5-(3'-chloro-4'-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(3'-Chloro-p-toluoyl)-1-methylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce6-methyl-5-(3'-chloro-4'-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3'-chloro-4'-methylphenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 14

6-Methyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Methyl 5-(3',4'-dimethoxybenzoyl)-1-methylpyrrole-2-acetate

By repeating the Friedel-Crafts procedures of Example 11 with anequivalent amount of an appropriately substituted benzoyl chloride,methyl 5-(3',4'-dimethoxybenzoyl)-1-methylpyrrole-2-acetate is obtained.

(B) The transformation of the acetic acid ester of part (A) to itsacetic acid is performed according to example 11 part B to yield5-(3',4'-dimethoxybenzoyl)-1-methylpyrrole-2-acetic acid

(D)6-Methyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The acid from part B above is subjected to the procedure of Example 1,part C to produce6-methyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3',4'-dimethoxyphenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 156-Methyl-5-(3',5'-Dinitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Methyl 5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetate

By repeating the Friedel-Crafts procedures of Example 11 with anequivalent amount of an appropriately substituted benzoyl chloride,methyl 5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetate.

(B) 5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetic acid

The transformation of the acetic acid ester of part (A) to its aceticacid is performed according to the hydrolysis procedure of Example 11Bis repeated with an equivalent amount of the pyrrole acetate obtained inpart (A) to yield 5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-aceticacid.

(C)6-Methyl-5-(3',5'-dinitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce6-methyl-5-(3',5'-dinitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3',5'-dinitrophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 166-Methyl-5-(3'-Bromo-4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Methyl 5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acetate

By repeating the Friedel-Crafts procedures of Example 11with anequivalent amount of an appropriately substituted benzoyl chloride,methyl 5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acetate isobtained.

(B) 5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acetic acid

The transformation of the acetic acid ester of part (A) to its aceticacid is performed according to the hydrolysis procedure of Example 11Bis repeated with an equivalent amount of the pyrrole acetate obtained inpart (A) to yield 5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-aceticacid.

(C)6-Methyl-5-(3'-Bromo-4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to produce6-methyl-5-(3'-Bromo-4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3'-bromo-4'-chlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 176-Methyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Methyl 5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-acetate

By repeating the Friedel-Crafts procedures of Example 11 with anequivalent amount of an appropriately substituted benzoyl chloride,methyl 5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-acetate isobtained.

(B) 5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-acetic acid

The transformation of the acetic acid ester of part (A) to its aceticacid is performed according to the hydrolysis procedure of Example 11Bis repeated with an equivalent amount of the pyrrole acetate obtained inpart (A) to yield 5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-aceticacid.

(C)6-Methyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to produce6-methyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =2',3',5'-tribromophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 186-Methyl-5-(3',4',5'-Trimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Methyl 5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetate

By repeating the Friedel-Crafts procedures of Example 11 with anequivalent amount of an appropriately substituted benzoyl chloride,methyl 5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetate isobtained.

(B) 5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetic acid

The transformation of the acetic acid ester of part (A) to its aceticacid is performed according to the hydrolysis procedure of Example 11Bis repeated with an equivalent amount of the pyrrole acetate obtained inpart (A) to yield5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetic acid.

(C)6-Methyl-5-(3',4',5'-trimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to produce6-methyl-5-(3',4',5'-trimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3',4',5'-trimethoxyphenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 196-Methyl-5-(p-Acetaminobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Nitrobenzoyl)-1-methylpyrrole-2-acetonitrile

A solution of 46.4 g. (0.25 mole) of p-nitrobenzoyl chloride in 100 ml.1,2-dichloroethane is added portionwise to a suspension of 32.2 g. (0.25mole) aluminum cloride in 100 ml. 1,2-dichloroethane. This mixture isadded dropwise to a chilled solution of 30.0 g. (0.25 mole)1-methylpyrrole-2-acetonitrile in 100 ml. 1,2-dichloroethane. After theaddition is complete, the mixture is stirred for twenty minutes at roomtemperature and then refluxed for four minutes. It is poured into iceacidified with 2N hydrochloric acid. The organic phase is separated andwashed successively with N,N-dimethyl-1,3-propanediamine, 3Nhydrochloric acid and saturated sodium chloride solution. It is thendried over magnesium sulfate and the solvent evaporated in vacuo. Theresulting semi-solid residue is triturated with cold methanol from whichthe product, 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetonitrile,crystallizes. It is removed by filtration and purified byrecrystallization from acetone, m.p. 167-169° C.

(B) 5-(p-Aminobenzoyl)-1-methylpyrrole-2-acetonitrile

A solution of 7 g. (0.026 mole) of5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetonitrile in 450 ml. of ethylacetate containing 1 g. palladium-on-carbon catalyst is hydrogenated ina Parr shaker under 44 p.s.i. of hydrogen until the theoretical amountof hydrogen is consumed. The catalyst is filtered off, and the solventevaporated in vacuo. A yellow solid,5-(p-aminobenzoyl)-1-methylpyrrole-2-acetonitrile remains, m.p. 137-142°C.

(C) 5-(p-Acetaminobenzoyl)-1-methylpyrrole-2-acetic acid

A suspension of 6.0 g. (0.025 mole) of5-(p-aminobenzoyl)-1-methylpyrrole-2-acetonitrile, 25 ml. 95% ethanoland 25 ml./N sodium hydroxide is refluxed overnight. The ethanol is thenevaporated in vacuo, and the remaining suspension is poured into iceacidified with dilute hydrochloric acid to pH 5. The resulting solid ispartitioned between sodium bicarbonate solution and chloroform. Theinsoluble substances are filtered from the two-phase mixture. The sodiumbicarbonate layer is separated and acidified slowly with dilutehydrochloric acid. Solids precipitate at various pHs which are separatedby filtration. The desired product,5-(p-aminobenzoyl)-1-methylpyrrole-2-acetic acid, precipitates at pH 3,m.p. 173-175° C. Acylation with acetic anhydride in pyridine yields thetitle compound.

(D)6-Methyl-5-(p-Acetaminobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Acetaminobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(p-aminobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁=H, R₂ =H, R₃ =p-acetaminophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 206-Methyl-5-(p-Nitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-Nitrobenzyl)-1-methylpyrrole-2-acetate

A solution of 5.5 g. (0.03 mole) of p-nitrobenzoyl chloride in 60 ml.methylene chloride is added to a suspension of 3.9 g. (0.03 mole)aluminum chloride in 20 ml. methylene chloride. The resulting suspensionis added dropwise to a chilled (-15° C.) solution of ethyl1-methylpyrrole-2-acetate in 50 ml. methylene chloride. The solution isstirred for 15 minutes at -10° C. and at room temperature for 15minutes. The reaction mixture is poured into ice-dilute hydrochloricacid. The organic phase is separated and washed successively withN,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and a saturatedsolution of sodium chloride, dried over anhydrous magnesium sulfate, andthe solvent evaporated in vacuo. A solid, ethyl5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetate, crystallizes from theremaining oily residue which is isolated by recrystallization frommethanol, m.p. 103-106° C.

(B) 5-(p-Nitrobenzoyl)-1-methylpyrrole-2-acetic acid

A solution of 3.2 g. (0.01 mole) of ethyl5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetate and 25 ml. ethanol isbrought to reflux. To this is added dropwise 10 ml. of 1N sodiumhydroxide solution. After the addition is complete, the ethanol isevaporated and the residue is acidified with dilute hydrochloric acid.The resulting solid, 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetic acid,is separated by filtration and purified by recrystallization fromethanol, m.p. 192-195° C.

(C) 6-Methyl-5-(p-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Nitrobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(p-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁=H, R₂ =H, R₃ =p-nitrophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 216-Methyl-5-(p-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate

A solution of 5.0 g. (0.03 mole) of p-cyanobenzoyl chloride in 60 ml. ofmethylene chloride is added to a suspension of 40 g. of aluminumchloride in 30 ml. methylene chloride. The resulting mixture is addeddropwise to a chilled solution of 5.0 g. (0.03 mole) of ethyl1-methylpyrrole-2-acetate in 15 ml. of methylene chloride. The resultingmixture is stirred at room temperature for 20 minutes, and then pouredinto ice acidified with dilute hydrochloric acid. The organic phase isseparated, washed successively with N,N-dimethylaminopropylamine, 3Nhydrochloric acid and brine, and dried over anhydrous magnesium sulfate.The solvent is evaporated in vacuo. The resulting solid, which separatesfrom the oily residue on standing, is recrystallized from methanol togive pure ethyl 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate, m.p.117-120° C.

(B) 5-(p-Cyanobenzoyl)-1-methylpyrrole-2-acetic acid

A solution of 0.5 g. (0.0017 mole) of ethyl5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate in 3 ml. ethanol is broughtto reflux and 1.7 ml. of 1N sodium hydroxide solution is added dropwise.The mixture is refluxed for 3 minutes, and the ethanol is thenevaporated in vacuo. The residue is diluted with water and acidifiedwith dilute hydrochloric acid. A white solid precipitates,5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetic acid, which is collected byfiltration and dried, m.p. 196-198° C.

(C) 6-Methyl-5-(p-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Cyanobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(p-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁=H, R₂ =H, R₃ =p-cyanophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 22Rac-1,6-Dimethyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetate

A solution of 6.68 g. (0.0219 mole) of ethyl5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate in 50 ml. of ether isadded to a solution of 0.94 g. (0.024 mole) of sodamide in about 150 ml.of liquid ammonia at -33° C. The mixture is allowed to reflux for 15minutes and 3.10 g. (0.0219 mole) of methyl iodide is added. The mixtureis stirred for one hour; then the ammonia is allowed to boil off. Etherand enough ammonium chloride to neutralize any anion are added. Themixture is poured into dilute hydrochloric acid and the ether solutionis separated and washed with sodium bisulfite solution, sodiumbicarbonate solution and brine. It is dried over anhydrous magnesiumsulfate and evaporated to give an oily residue which crystallizes uponstanding. The solid is recrystallized successively from cyclohexane andmethanol to give a white crystalline solid, ethyl5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetate, m.p. 67-68° C.

(B) 5-(p-Chlorobenzyl)-α-methyl-1-methylpyrrole-2-acetic acid

A solution of 4.05 g. (0.0126 mole) of ethyl5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetate, 15 ml. of 1Nsodium hydroxide solution and 2 ml. of ethanol is refluxed for 30minutes. The solution is cooled, diluted with water and filtered. Thefiltrate is acidified with dilute hydrochloric acid. The precipitatedsolid is collected and recrystallized from methanol-water to give awhite crystalline solid,5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid, m.p.135-136° C. Analysis: Calcd. for C₁₅ H₁₄ ClNO₃ : C, 61.76; H, 4.83; N,4.82% Found: C, 61.68: H, 4.86; N, 4.89%

(C) 5-(p-Chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetonitrile

To a suspension of sodium hydride (12.2 g. of 50% w/w NaH in mineraloil) in 1,2-dimethoxyethane is added5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile (62.6 g., 0.24 mole)in 1,2-dimethoxyethane over a period of 1/2 hr. at room temperature.After the addition is complete, the mixture is stirred for 1 hour andthen 35 g. (0.25 mole) of methyl iodide is added. The reaction mixtureis stirred for an additional 3 hours, concentrated under reducedpressure, diluted with water and extracted with chloroform. Afterdrying, the chloroform is removed leaving a brown solid residue which istriturated with cold methanol to give yellow crystals of5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetonitrile, m.p.145-148° C. Two recrystallizations from methanol raises the m.p. to151.5-152.5° C.

(D) 5-(p-Chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid

27.1 g. (0.1 mole) sample of5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetonitrile ishydrolyzed by refluxing for 16 hours with 8 g. (0.2 mole) of sodiumhydroxide in 350 ml. of aqueous ethanol. Upon concentration in vacuo,the sodium salt separates which is filtered off and dissolved in water.After acidification with dilute HCl, the corresponding acid,5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid,precipitates. The original basic filtrates are also acidified, extractedwith chloroform and concentrated. The residual solid is combined withthe previous solid and recrystallized from methanol-water to give thepure product, 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-aceticacid, m.p. 139-141° C.

(E)Rac-1,6-dimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to yieldrac-1,6-dimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =CH₃, R₂ =H, R₃ =p-chlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 23Rac-1-Ethyl-6-Methyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Chlorobenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid

A solution of 6.5 g (0.021 mole) of ethyl5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate in 60 ml. of ether isadded to a suspension of 1.25 g. (0.032 mole) of sodamide in 150 ml. ofrefluxing liquid ammonia. After 10 minutes, 4.98 g. (0.032 mole) ofethyl iodide is added. The mixture is stirred for 1.5 hours, and anadditional 1.0 g. (0.0064 mole) of ethyl iodide is added. Stirring iscontinued for 30 minutes and ammonium chloride is then added toneutralize any anion. The mixture is allowed to warm to room temperatureand the ammonia allowed to escape. Ether is added, and the mixturepoured into dilute hydrochloric acid. The ether layer is separated, andthe aqueous layer is washed with ether. The combined ether solutions arewashed successively with sodium bisulfite solution and brine and thendried over anhydrous magnesium sulfate. The solvent is evaporated invacuo to give about 7.4 g. of a yellow oily residue containing ethyl5-(p-chlorobenzoyl)-α-ethyl-1-methylpyrrole-2-acetate, which is used assuch in the following transformation to acid procedure. A 6.9 g. sampleof the oily residue is dissolved in 30 ml. of ethanol and 11.4 ml. of 1Nsodium hydroxide is added. The mixture is refluxed for 1 hour. Thesolvent is then evaporated in vacuo, and the residue partitioned betweenether and water. The aqueous layer is separated and acidified withdilute hydrochloric acid. The precipitated oil, which is separated,crystallizes on scratching to give a solid,5-(p-chlorobenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid, which iscollected and dried, m.p. 108-112° C. After successiverecrystallizations from ether-methylcyclohexane, benzene-hexane,methylcyclohexane and ether-hexane, the m.p. is 110-114° C. Analysis:Calcd. for C₁₆ H₁₆ ClNO₃ : C, 62.84; H, 5.27; N, 4.58% Found: C, 63.01;H, 5.36; N, 4.61%

(B)Rac-1-ethyl-6-methyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1-ethyl-6-methyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =ethyl, R₂ =H, R₃ =p-chlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1 , n=0).

EXAMPLE 24Rac-1-(n-Butyl)-6-Methyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-Benzoyl-α-(N-butyl)-1-methylpyrrole-2-acetic acid

The alkylation and ester-to-acid transformation procedures of Example 23are repeated except that an equivalent amount of an appropriate5-Aryl-1-methylpyrrole-2-acetic acid alkyl ester and an equivalentamount of an appropriate alkyl halide alkylating agent are employed toyield 5-benzoyl-α-(n-butyl)-1-methylpyrrole-2-acetic acid.

(B)Rac-1-(n-butyl)-6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-Benzoyl-α-(n-butyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to producerac-1-(n-butyl)-6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-butyl, R₂ =H, R₃ =phenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 25Rac-1,6-Dimethyl-5-(4'-Methoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Methoxybenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid

The alkylation and ester-to-acid transformation procedures of Example 23are repeated except that an equivalent amount of an appropriate5-Aryl-1-methylpyrrole-2-acetic acid alkyl ester and an equivalentamount of an appropriate alkyl halide alkylating agent are employed toyield 5-(p-methoxybenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid.

(B)Rac-1,6-dimethyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Methoxybenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1,6-dimethyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =CH₃, R₂ =H, R₃ =4'-methoxyphenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 26Rac-1-(n-Propyl)-6-Methyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-Benzoyl-α-(n-propyl)-1-methylpyrrole-2-acetic acid

The alkylation and ester-to-acid transformation procedures of Example 23are repeated except that an equivalent amount of an appropriate5-Aryl-1-methylpyrrole-2-acetic acid alkyl ester and an equivalentamount of an appropriate alkyl halide alkylating agent are employed toyield 5-benzoyl-α-(n-propyl)-1-methylpyrrole-2-acetic acid.

(B)Rac-1-(n-propyl)-6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-Benzoyl-α-(n-propyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to producerac-1-(n-propyl)-6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =phenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 27Rac-1,6-Dimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Cyanobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid

The alkylation and ester-to-acid transformation procedures of Example 23are repeated except that an equivalent amount of an appropriate5-Aryl-1-methylpyrrole-2-acetic acid alkyl ester and an equivalentamount of an appropriate alkyl halide alkylating agent are employed toyield 5-(p-cyanobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid.

(B)Rac-1,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Cyanobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to produce (R₁ =CH₃, R₂ =H, R₃=4'-cyanophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 28Rac-1,6-Dimethyl-5-(3'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(m-Chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid

The alkylation and nitrile-to-acid transformation procedures of Examples22C and 22D, respectively, are repeated except that an equivalent amountof an appropriate 5-Aryl-1-methylpyrrole-2-acetonitrile and anequivalent amount of an appropriate alkyl halide alkylating agent areemployed to yield 5-(m-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-aceticacid.

(B)Rac-1,6-dimethyl-5-(3'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(m-Chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1,6-dimethyl-5-(3'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =CH₃, R₂ =H, R₃ =3'-chlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 29Rac-1-Ethyl-6-Methyl-5-(4'-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Fluorobenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid

The alkylation and nitrile-to-acid transformation procedures of Examples22C and 22D, respectively, are repeated except that an equivalent amountof an appropriate 5-Aryl-1-methylpyrrole-2-acetonitrile and anequivalent amount of an appropriate alkyl halide alkylating agent areemployed to yield 5-(p-fluorobenzoyl)-α-ethyl-1-methylpyrrole-2-aceticacid.

(B)rac-1-ethyl-6-methyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Fluorobenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1-ethyl-6-methyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =ethyl, R₂ =H, R₃ =4'-fluorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 30Rac-1,6-Dimethyl-5-(4'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Methylbenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid

The alkylation and nitrile-to-acid transformation procedures of Examples22C and 22D, respectively, are repeated except that an equivalent amountof an appropriate 5-Aryl-1-methylpyrrole-2-acetonitrile and anequivalent amount of an appropriate alkyl halide alkylating agent areemployed to yield 5-(p-methylbenzoyl)-α-ethyl-1-methylpyrrole-2-aceticacid.

(B)rac-1,6-dimethyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Methylbenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1,6-dimethyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =CH₃, R₂ =H, R₃ =4'-Methylphenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 31Rac-1,6-Dimethyl-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(2',4'-Dichlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid

The alkylation and nitrile-to-acid transformation procedures of Examples22C and 22D, respectively, are repeated except that an equivalent amountof an appropriate 5-Aryl-1-methylpyrrole-2-acetonitrile and anequivalent amount of an appropriate alkyl halide alkylating agent areemployed to yield5-(2',4'-dichlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid.

(B)rac-1,6-dimethyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2',4'-Dichlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1,6-dimethyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =CH₃, R₂ =H, R₃ =2',4'-dichlorophenyl, R₄ =CH₃, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 32Rac-1-Ethyl-6-Methyl-5-(3'-Chloro-4'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(3'-Chloro-4'-methylbenzoyl)-α-ethyl-1-methylpyrrole-2-aceticacid.

The alkylation and nitrile-to-acid transformation procedures of Examples22C and 22D, respectively, are repeated except that an equivalent amountof an appropriate 5-Aryl-1-methylpyrrole-2-acetonitrile and anequivalent amount of an appropriate alkyl halide alkylating agent areemployed to yield5-(3'-chloro-4'-methylbenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid.

(B)rac-1-ethyl-6-methyl-5-(3'-chloro-4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(3'-Chloro-4'-methylbenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-ethyl-6-methyl-5-(3'-chloro-4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =CH₃, R₂ =H, R₃ =3'-Chloro-4'-Methylphenyl, R₄ =CH₃, R₅ =H, Y=CO,m=1, n=0).

EXAMPLE 33 5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Chlorobenzoyl)-pyrrole-2-acetonitrile

To a chilled suspension of 26.80 g. (0.2 mole) of aluminum chloride in110 ml. of methylene chloride is added dropwise 35 g. (0.2 mole) ofp-chlorobenzoyl chloride. The mixture is added dropwise to a solution of21.22 g. (0.2 mole) of pyrrole-2-acetonitrile in 125 ml. methylenechloride which is cooled externally with an ammonium chloride ice bath.After addition is complete, the reaction mixture is stirred for tenminutes at 0° C. and then poured into ice acidified with dilutehydrochloric acid. A solid precipitate,5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile, which is filtered off,washed with hot methanol and dried, m.p. 203-205° C.

(B) 5-(p-Chlorobenzoyl)-pyrrole-2-acetic acid

A solution of 3.6 g. (0.015 mole) of5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile, 30 ml. 1N sodium hydroxidesolution, and 30 ml. 95% ethanol is refluxed and stirred for 6 hours.The ethanol is evaporated off in vacuo. The resulting solid is dissolvedin water and the solution filtered from insolubles. The filtrate isacidified with dilute hydrochloric acid. A white solid precipitates,5-(p-chlorobenzoyl)-pyrrole-2-acetic acid, which is purified byrecrystallization from acetone water (1:1), m.p. 210° C.

(C) BOC 5-(p-chlorobenzoyl)-pyrrole-2-acetic acid

The pyrrole nitrogen is protected with the t-butyl carbamate groupemploying (BOC)₂ O as a reagent according to D. S. Tarbell Proc. Natl.Acad. Sci (USA), 69, 730 (1972).

(D) BOC 5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalene-2-one

BOC 5-(p-chlorobenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce BOC5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

(C) 5-(4'-Chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalene-2-one

The BOC group is removed from the BOC-lactone employing trifluoroaceticacid as a reagent according to Y. Masui, Bull. Chem. Soc. Japan 53, 464(1980)(R₁ =H, R₂ =H, R₃ =4'-chlorophenyl, R₄ =H, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 34 5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-Benzoyl-pyrrole-2-acetonitrile

The procedure of Example 33A is repeated, except that an equivalentamount of an appropriate benzoyl chloride is used in place of thep-chlorobenzoyl chloride used therein 5-benzoyl-pyrrole-2-acetonitrileis obtained.

(B) 5-Benzoyl-pyrrole-2-acetic acid

The procedure of Example 33B is repeated using an equivalent amount of5-benzoyl-pyrrole-2-acetonitrile obtained in part A of this Example inplace of 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile to yield5-benzoyl-pyrrole-2-acetic acid.

(C) BOC 5-benzoyl-pyrrole-2-acetic acid

The procedure of Example 33C is repeated using5-benzoyl-pyrrole-2-acetic acid to produce BOC5-benzoyl-pyrrole-2-acetic acid.

(D) BOC 5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

BOC 5-benzoyl-pyrrole-2-acetic acid is subjected to the procedure ofExample 1, part C to produce BOC5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(E) 5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using BOC5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to produce5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H, R₂ =H, R₃=phenyl, R₄ =H, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 35 5-(p-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Fluorobenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 33A is repeated, except that an equivalentamount of an appropriate benzoyl chloride is used in place of thep-chlorobenzoyl chloride used therein to give5-(p-fluorobenzoyl)-pyrrole-2-acetonitrile.

(B) 5-(p-Fluorobenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33B is repeated using an equivalent amount of5-(p-fluorobenzoyl)-pyrrole-2-acetonitrile obtained in part A of thisExample in place of 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile to yield5-(p-fluorobenzoyl)-pyrrole-2-acetic acid.

(C) BOC 5-(p-fluorobenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33C is repeated using5-(p-fluorobenzoyl)-pyrrole-2-acetic acid to give BOC5-(p-fluorobenzoyl)-pyrrole-2-acetic acid.

(D) BOC 5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

BOC 5-(p-fluorobenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce BOC5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(E) 5-(p-Fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using BOC5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to give5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H, R₂=H, R₃ =4'-fluorophenyl, R₄ =H, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 36 5-(p-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-methylbenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 33A is repeated, except that an equivalentamount of an appropriate benzoyl chloride is used in place of thep-chlorobenzoyl chloride used therein5-(p-methylbenzoyl)-pyrrole-2-acetonitrile is obtained.

(B) 5-(p-Methylbenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33B is repeated using an equivalent amount ofeach pyrrole-acetonitrile obtained in part A of this Example in place of5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile to yield5-(p-methylbenzoyl)-pyrrole-2-acetic acid.

(C) BOC 5-(p-methylbenzoyl)-pyrrole-2-acetic acid.

The procedure of Example 33C is repeated using5-(p-methylbenzoyl)-pyrrole-2-acetic acid to give BOC5-(p-methylbenzoyl)-pyrrole-2-acetic acid

(D) BOC 5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

BOC 5-(p-methylbenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce BOC5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(E) 5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using produce BOC5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to yield5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H, R₂=H, R₃ =4'-methylphenyl, R₄ =H, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 37 5-(p-Methoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-methoxybenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 33A is repeated, except that an equivalentamount of an appropriate benzoyl chloride is used in place of thep-chlorobenzoyl chloride used therein5-(p-methoxybenzoyl)-pyrrole-2-acetonitrile is obtained.

(B) 5-(p-methoxybenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33B is repeated using an equivalent amount of5-(p-methoxybenzoyl)-pyrrole-2-acetonitrile obtained in part A of thisExample in place of 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile to yield5-(p-methoxybenzoyl)-pyrrole-2-acetic acid.

(C) BOC 5-(p-methoybenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33C is repeated using5-(p-methoxybenzoyl)-pyrrole-2-acetic acid to give BOC5-(p-methoybenzoyl)-pyrrole-2-acetic acid.

(D) BOC 5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

BOC 5-(p-methoxybenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce BOC5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(E) 5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using BOC5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to produce5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H, R₂=H, R₃ =4'-methoxyphenyl, R₄ =H, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 385-(3'-Chloro-4'-Methoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(3'-chloro-4'-methoxybenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 33A is repeated, except that an equivalentamount of an appropriate benzoyl chloride is used in place of thep-chlorobenzoyl chloride used therein to give5-(3'-chloro-4'-methoxybenzoyl)-pyrrole-2-acetonitrile.

(B) 5-(3'-Chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33B is repeated using an equivalent amount of5-(3'-chloro-4'-methoxybenzoyl)-pyrrole-2-acetonitrile obtained in partA of this Example in place of 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrileto yield 5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid.

(C) BOC 5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33C is repeated using5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid to yield BOC5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid.

(D) BOC5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

BOC 5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce BOC5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(E)5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using BOC5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-oneto yield5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3'-chloro-4'-methylphenyl, R₄ =H, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 395-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 33A is repeated, except that an equivalentamount of an appropriate benzoyl chloride is used in place of thep-chlorobenzoyl chloride to give5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile.

(B) 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33B is repeated using an equivalent amount of5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile obtained in part A ofthis Example in place of 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile toyield 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid.

(C) BOC 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid

The procedure of Example 33C is repeated using5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid to produce BOC5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid.

(D) BOC5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

BOC 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce BOC5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(E) 5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using BOC5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one toyield 5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =2', 4'-dichlorophenyl, R₄ =H, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 406-Ethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetonitrile

A mixture of 24.4 g. (0.1 mole)5-(p-chlorobenzyl)-pyrrole-2-acetonitrile, 41.7 g. (0.3 mole) ofpotassium carbonate and 16.1 g. (0.1 05 mole) of ethyl iodide in 300 ml.of methylethylketone is refluxed overnight. The reaction mixture is thenpoured into water and extracted with chloroform. The organic solutionsare combined, dried over anhydrous magnesium sulfate, and the solventevaporated in vacuo. The residue is crystallized from 2-propanol to giveabout 13 g. of crude solid. The solid is sublimed overnight at 140° C.and 0.025 mm. Hg. The sublimate is successively recrystallized from2-propanol, benzene and hexane to give5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetonitrile as a white solid, m.p.145-147° C. Analysis: Calcd. for C₁₅ H₁₃ ClN₂ O: N, 10.2%. Found: N,10.54%.

(B) 5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetic acid

A suspension of 3.52 g. (0.013 mole) of5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetonitrile in 26 ml. 1N sodiumhydroxide and 50 ml. of ethanol is refluxed for six hours. The mixtureis then diluted with water and cooled. A solid precipitates which isfiltered off and set aside. The ethanol is evaporated from the filtratein vacuo. The collected precipitate is added to the concentratedfiltrate, and the mixture is extracted with chloroform. The aqueousphase is separated, acidified with dilute hydrochloric acid, and theresulting precipitate (A) is collected by filtration and dried. Thechloroform phase is evaporated and the residue refluxed with 12 ml. of1N sodium hydroxide and 24 ml. of ethanol for 6 hours. The ethanol isevaporated in vacuo, and the remaining solution is diluted with waterand washed with chloroform. The aqueous solution is acidified withdilute hydrochloric acid and the precipitated solid (B) is collected anddried. The two samples of acidic material (A and B) are combined andrecrystallized from aqueous isopropanol to give5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetic acid as a white solid, m.p.149-153° C. Analysis: Calcd. for C₁₅ H₁₄ ClNO₃ : C, 61.75; H, 4.83; N,4.80%. Found: C, 61.78; H, 4.94; N, 4.96%.

(C)6-ethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-1-ethylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to yield6-ethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-chlorophenyl, R₄ =ethyl, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 416-(n-Propyl)-5-(4'-Methylphenyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetonitrile

The N-alkylation procedure of Example 40A is followed with an equivalentamount of N-unsubstituted 5-(p-methylbenzoyl)-pyrrole-2-acetonitrile andan equivalent amount of n-propyl iodide as the N-alkylating agent, toyield 5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetonitrile.

(B) 5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 40B is repeated,except that an equivalent amount of the acetonitrile obtained in part Aof this Example is used as the starting acetonitrile to yield5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetic acid.

(C)6-(n-propyl)-5-(4'-methylphenyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce6-(n-propyl)-5-(4'-methylphenyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-methylphenyl, R₄ =n-propyl, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 426-Ethyl-5-(4'-Methoxyphenyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetonitrile

The N-alkylation procedure of Example 40A is followed with an equivalentamount of N-unsubstituted 5-(p-methoxybenzoyl)-pyrrole-2-acetonitrileand an equivalent amount of ethyl iodide as the N-alkylating agent, toyield 5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetonitrile.

(B) 5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 40B is repeated,except that an equivalent amount of the acetonitrile obtained in part Aof this Example is used as the starting acetonitrile to yield5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetic acid.

(C)6-ethyl-5-(4'-methoxyphenyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-ethyl-5-(4'-methoxyphenyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-methoxyphenyl, R₄ =ethyl, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 436-(n-Butyl)-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetonitrile

The N-alkylation procedure of Example 40A is followed with an equivalentamount of N-unsubstituted5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile and an equivalentamount of n-butyl iodide as the N-alkylating agent, to yield5-benzoyl-1-ethylpyrrole-2-acetonitrile5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetonitrile.

(B) 5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 40B is repeated,except that an equivalent amount of the acetonitrile obtained in part Aof this Example is used as the starting acetonitrile to yield5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetic acid.

(C)6-(n-butyl)-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to produce6-(n-butyl)-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =2',4'-dichlorophenyl, R₄ =n-butyl, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 44 6-Ethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-benzoyl-1-ethylpyrrole-2-acetonitrile

The N-alkylation procedure of Example 40A is followed with an equivalentamount of N-unsubstituted 5-benzoyl -pyrrole-2-acetonitrile and anequivalent amount of ethyl iodide as the N-alkylating agent, to yield5-benzoyl-1-ethylpyrrole-2-acetonitrile.

(B) 5-benzoyl-1-ethylpyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 40B is repeated,except that an equivalent amount of the acetonitrile obtained in part Aof this Example is used as the starting acetonitrile to yield5-benzoyl-1-ethylpyrrole-2-acetic acid.

(C) 6-ethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-benzoyl-1-ethylpyrrole-2-acetic acid is subjected to the procedure ofExample 1, part C to produce6-ethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H, R₂=H, R₃ =phenyl, R₄ =ethyl, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 45Rac-1-Methyl-6-Ethyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-chlorobenzoyl)-α-methyl-1-ethylpyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount of thealkylpyrrole-acetonitrile obtained in Example 40 is used in place of thestarting acetonitrile used in Example 22C, and an equivalent amount ofmethyl iodide is used as the alkylating agent, to yield5-(p-chlorobenzoyl)-α-methyl-1-ethylpyrrole-2-acetic acid.

(B)rac-1-methyl-6-ethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-chlorobenzoyl)-α-methyl-1-ethylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1-methyl-6-ethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =p-chlorophenyl, R₄ =ethyl, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 46Rac-1-Methyl-6-Ethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalene-2-One

(A) 5-benzoyl-α-methyl-1-ethylpyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount ofalkylpyrrole-acetonitrile obtained in Example 44 is used in place of thestarting acetonitrile used in Example 22C, and an equivalent amount ofmethyl iodide is used as the alkylating agent, to yield5-benzoyl-α-methyl-1-ethylpyrrole-2-acetic acid.

(B)rac-1-methyl-6-ethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalene-2-one

5-benzoyl-α-methyl-1-ethylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to producerac-1-methyl-6-ethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalene-2-one(R₁ =methyl, R₂ =H, R₃ =phenyl, R₄ =ethyl, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 47Rac-1-Ethyl-6-(n-Propyl)-5-(p-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-methylbenzoyl)-α-ethyl-1-(n-propyl)pyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount ofalkylpyrrole-acetonitrile obtained in Example 41 is used in place of thestarting acetonitrile used in Example 22C, and an equivalent amount ofethyl iodide is used as the alkylating agent, to yield5-(p-methylbenzoyl)-α-ethyl-1-(n-propyl)pyrrole-2-acetic acid.

(B)rac-1-ethyl-6-(n-propyl)-5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-methylbenzoyl)-α-ethyl-1-(n-propyl)pyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-ethyl-6-(n-propyl)-5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =ethyl, R₂ =H, R₃ =4'-methylphenyl, R₄ =n-propyl, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 48Rac-1-Methyl-6-(n-Butyl)-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(2',4'-Dichlorobenzoyl)-α-methyl-1-(n-butylpyrrole)-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount ofalkylpyrrole-acetonitrile obtained in Example 43 is used in place of thestarting acetonitrile used in Example 22C, and an equivalent amount ofmethyl iodide is used as the alkylating agent, to yield5-(2',4'-dichlorobenzoyl)-α-methyl-1-(n-butylpyrrole)-2-acetic acid

(B)rac-1-methyl-6-(n-butyl)-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2',4'-dichlorobenzoyl)-α-methyl-1-(n-butylpyrrole)-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-methyl-6-(n-butyl)-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =2',4'-dichlorophenyl, R₄ =n-butyl, R₅ =H, Y=CO,m=1, n=0).

EXAMPLE 496-Benzyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile

A solution of 8.43 ml. (0.0663 mole) of p-chlorobenzoyl chloride and 8.8g. (0.0663 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethaneis added to a solution of 13.0 g. (0.0663 mole) of1-benzylpyrrole-2-acetonitrile in 50 ml. of 1,2-dichloroethane at 5° C.over a 5 minute period. The mixture is stirred for 15 minutes, and thenheated quickly to reflux for 3 minutes. The reaction mixture is pouredinto ice-hydrochloric acid and then filtered. The aqueous layer isseparated and washed with chloroform. The combined organic solutions arewashed successively with N,N-dimethylaminopropylamine solution, dilutehydrochloric acid, and brine and then dried over anhydrous magnesiumsulfate. The solvent is evaporated and the oily residue dissolved inbenzene-methylcyclohexane and seeded with crystals of1-benzyl-4-(p-chlorobenzoyl)-pyrrole-2-acetonitrile. Aftercrystallization of the latter substance is complete, the mother liquoris filtered and evaporated and the residue crystallized from methanol.The crystals thus obtained are recrystallized from methanol to give1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile as a yellow solid,m.p. 104-106° C.

(B) 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid

A suspension of 3.0 g. (0.009 mole) of1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile in 20 ml. of ethanoland 18 ml. (0.018 mole) of 1N sodium hydroxide is refluxed for 6 hours.The mixture is diluted with water, and the ethanol evaporated in vacuo.The solution is washed with chloroform and ether and acidified with 3Nhydrochloric acid. The precipitated solid is collected and dried invacuo to give 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid aswhite crystals, M.P. 162-163° C. Analysis: Calcd. for C₂₀ H₁₅ ClNO₃ : C,67.70; H, 4.65; N, 3.96%. Found: C, 67.79; H, 4.65; N, 3.97%.

(C)6-benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-chlorophenyl, R₄ =phenyl, R₅ =H, Y=CO, CH₂, m=1,n=1).

EXAMPLE 50 5-Benzoyl-6-Benzyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-benzyl-5-benzoyl-pyrrole-2-acetonitrile

The procedure of Example 49 is followed with an equivalent amount ofbenzoyl chloride in place of the p-chlorobenzoyl chloride used thereinto yield 1-benzyl-5-benzoyl-pyrrole-2-acetonitrile.

(B) 1-benzyl-5-benzoyl-pyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 49B is followedusing an equivalent amount of the acetonitrile obtained in part A ofthis Example to yield 1-benzyl-5-benzoyl-pyrrole-2-acetic acid.

(C) 5-benzoyl-6-benzyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-benzyl-5-benzoyl-pyrrole-2-acetic acid is subjected to the procedureof Example 1, part C to produce5-benzoyl-6-benzyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H, R₂=H, R₃ =phenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂, m=1, n=1).

EXAMPLE 516-Benzyl-5-(4'-Bromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 49 is followed with an equivalent amount ofp-bromo benzoyl chloride in place of the p-chlorobenzoyl chloride usedtherein to yield 1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetonitrile.

(B) 1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 49B is followedusing an equivalent amount of the acetonitrile obtained in part A ofthis Example to yield 1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetic acid.

(C)6-benzyl-5-(4'-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-benzyl-5-(4'-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-bromophenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂, m=1,n=1).

EXAMPLE 526-Benzyl-5-(4'-Ethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 49 is followed with an equivalent amount ofp-ethoxy benzoyl chloride in place of the p-chlorobenzoyl chloride usedtherein to yield 1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetonitrile.

(B) 1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 49B is followedusing an equivalent amount of the acetonitrile obtained in part A ofthis Example to yield 1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-aceticacid.

(C)6-benzyl-5-(4'-ethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-benzyl-5-(4'-ethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-ethoxyphenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂, m=1,n=1).

EXAMPLE 536-Benzyl-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 49 is followed with an equivalent amount of2',4'-dichlorobenzoyl chloride in place of the p-chlorobenzoyl chlorideused therein to yield1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile.

(B) 1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 49B is followedusing an equivalent amount of the acetonitrile obtained in part A ofthis Example to yield1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid.

(C)6-benzyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce6-benzyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =2',4'-dichlorophenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂,m=1, n=1).

EXAMPLE 546-Benzyl-5-(3',4'-Dimethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetonitrile

The procedure of Example 49 is followed with an equivalent amount of3',4'-dimethylbenzoyl chloride in place of the p-chlorobenzoyl chlorideused therein to yield1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetonitrile.

(B) 1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 49B is followedusing an equivalent amount of the acetonitrile obtained in part A ofthis Example to yield1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetic acid.

(C)6-benzyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce6-benzyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3',4'-dimethylphenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂,m=1, n=1).

EXAMPLE 55Rac-1-Methyl-6-Benzyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-benzyl-5-(p-chlorobenzoyl)-α-methyl-pyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount of1-benzyl-5-(4'-chlorobenzoyl)-pyrrole-2-acetonitrile and an equivalentamount of methyl halide as the alkylating agent are used to yield1-benzyl-5-(p-chlorobenzoyl)-α-methyl-pyrrole-2-acetic acid.

(B)rac-1-methyl-6-benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Benzyl-5-(p-chlorobenzoyl)-α-methyl-pyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1-methyl-6-benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-chlorophenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂,m=1, n=1).

EXAMPLE 56Rac-1-(n-Propyl)-6-Benzyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-benzyl-5-benzoyl-α-(n-propyl)-pyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount of1-benzyl-5-benzoyl-pyrrole-2-acetonitrile and an equivalent amount ofn-propyl halide as the alkylating agent are used to yield1-benzyl-5-benzoyl-α-(n-propyl)-pyrrole-2-acetic acid.

(B)rac-1-(n-propyl)-6-benzyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Benzyl-5-benzoyl-α-(n-propyl)-pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to producerac-1-(n-propyl)-6-benzyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =phenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂, m=1,n=1).

EXAMPLE 57Rac-1-Ethyl-6-Benzyl-5-(4'-Bromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-Benzyl-5-(p-bromobenzoyl)-α-ethyl-pyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount of1-benzyl-5-(4'-bromobenzoyl)-pyrrole-2-acetonitrile and an equivalentamount of ethyl halide as the alkylating agent are used to yield1-benzyl-5-(p-bromobenzoyl)-α-ethyl-pyrrole-2-acetic acid.

(B)rac-1-ethyl-6-benzyl-5-(4'-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Benzyl-5-(p-bromobenzoyl)-α-ethyl-pyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1-ethyl-6-benzyl-5-(4'-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =ethyl, R₂ =H, R₃ =4'-bromophenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂,m=1, n=1).

EXAMPLE 58Rac-1-Methyl-6-Benzyl-5-(4'-Ethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-Benzyl -5-(p-ethoxybenzoyl)-α-methyl-pyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount of1-benzyl-5-(4'-ethoxybenzoyl)-pyrrole-2-acetonitrile and an equivalentamount of methyl halide as the alkylating agent are used to yield1-benzyl-5-(p-ethoxybenzoyl)-α-methyl-pyrrole-2-acetic acid.

(B)rac-1-methyl-6-benzyl-5-(4'-ethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-benzyl-5-(p-ethoxybenzoyl)-α-methyl-pyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1-methyl-6-benzyl-5-(4'-ethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-ethoxyphenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂,m=1, n=1).

EXAMPLE 59Rac-1-Ethyl-6-Benzyl-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-Benzyl-5-(2',4'-dichlorobenzoyl)-α-ethyl-pyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount of1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile and anequivalent amount of ethyl halide as the alkylating agent are used toyield 1-benzyl-5-(2',4'-dichlorobenzoyl)-α-ethyl-pyrrole-2-acetic acid.

(B)rac-1-ethyl-6-benzyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Benzyl-5-(2',4'-dichlorobenzoyl)-α-ethyl-pyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-ethyl-6-benzyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =ethyl, R₂ =H, R₃ =2',4'-dichlorophenyl, R₄ =phenyl, R₅ =H, Y=CO,X=CH₂, m=1, n=1).

EXAMPLE 60Rac-1-Methyl-6-Benzyl-5-(3',4'-Dimethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-Benzyl-5-(3',4'-dimethylbenzoyl)-α-methyl-pyrrole-2-acetic acid

The alkylation and transformation procedures of Examples 22C and 22D,respectively, are repeated, except that an equivalent amount of1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetonitrile and anequivalent amount of methyl halide as the alkylating agent are used toyield 1-benzyl-5-(3',4'-dimethylbenzoyl)-α-methyl-pyrrole-2-acetic acid.

(B)rac-1-Methyl-6-benzyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Benzyl-5-(3',4'-dimethylbenzoyl)-α-methyl-pyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-methyl-6-benzyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-oneR₁ =methyl R₂ =H, R₃ =3'4'-dimethylphenyl, R₄ =phenyl, R₅ =H, Y=CO,X=CH₂, M=1, n=1.

EXAMPLE 616-Methyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile

An acylating solution is prepared by the slow addition of 278 g. (1.58moles) of p-chlorobenzoyl chloride to 210 g. (1.58 moles) of aluminumchloride in 750 ml. of ethylene chloride. The resulting solution isadded to a solution of 190 g. (1.58 moles) ofN-methylpyrrole-2-acetonitrile in 750 ml. of ethylene chloride. Thetemperature is maintained at 20-22° C. during the addition; and thesolution is further stirred at room temperature for one hour. Thesolution is then heated rapidly to 74-76° C. at which point there is avigorous evolution of hydrogen chloride gas. This temperature ismaintained about 5 minutes, and the solution is cooled rapidly andpoured into ice water. The product is extracted with methylene chlorideand washed with water. The organic solution is then shaken with anexcess of an aqueous solution of N,N-dimethylaminopropylamine followedby dilute hydrochloric acid to remove any excess p-chlorobenzoylchloride. After a final wash with brine, the solution is dried overanhydrous magnesium sulfate. Distillation of the solvent leaves aresidue which crystallizes. Recrystallization from methyl alcohol yieldsthe product, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p.120-124° C. After two additional recrystallizations from methanol, them.p. is 127-131° C.

(B) 5-(p-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid

A mixture of 129 g. (0.52 mole) of5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile and 88 g. (1.1 moles)of 50% sodium hydroxide solution in 800 ml. of ethanol and 500 ml. ofwater is stirred and refluxed for about 18 hours with slow evolution ofammonia. The solution is then cooled to about 50° C. and acidified byadding 110 ml. of concentrated hydrochloric acid. The mixture is cooled,and the precipitated product,5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetic acid, is filtered andrecrystallized from methanol, m.p. 193-195° C. (dec.). A second crop isobtained upon concentration of the mother liquor for a total yield ofabout 67% of theoretical. Analysis: Calcd. for C₁₄ H₁₁ ClNO₃ : N, 5.05%.Found: N, 5.06%.

(C)6-Methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-chlorophenyl, R₄ =methyl, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 62 4-Methyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-Phenyl-1,2,3-butanetrione-2-oxime

The procedure described by Ceresole in Ber., 17, 815 (1884), wherein1-aryl-1,3-butanediones are reacted with nitrous acid to yield thecorresponding 1-aryl-1,2,3-butanetrione-2-oximes, is followed to prepare1-phenyl-1,2,3-butanetrione-2-oxime, m.p. 130-131° C.

(B) Ethyl 5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate

A solution of 71 g. (0.37 mole) of 1-phenyl-1,2,3-butanetrione-2-oximein 350 ml. glacial acetic acid and 50 ml. of water is added to 75.5 g.diethyl acetonedicarboxylate in 350 ml. of glacial acetic acid at 70° C.Concurrently, a mixture of 73 g. (1.12 mole) of zinc dust and 91.5 g.(1.12 mole) of anhydrous sodium acetate is added in portions at such arate that the temperature is maintained near 100° C. After the additionsare complete (about 45 minutes), the mixture is refluxed for one hourand poured into iced water. The resulting crude semisolid is collectedby filtration and recrystallized twice from methanol to give ethyl5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate, m.p. 152-154° C.Analysis: Calcd. for C₁₉ H₂₁ NO₅ : C, 66.46; H, 6.16; N, 4.08%. Found:C, 66.50; H, 6.20; N, 4.17%.

(C) 5-Benzoyl-3-carboxy-4-methylpyrrole-2-acetic acid

A mixture of 3.4 g. of ethyl5-benzoyl-3-ethoxy-carbonyl-4-methylpyrrole-2-acetate, 10 g. of 50%sodium hydroxide solution and 10 ml. of water is refluxed for 2 hours.The reaction mixture is then diluted with water and acidified withdilute hydrochloric acid. The precipitated solid is collected byfiltration, air-dried, and recrystallized from acetone-water to yieldthe product, 5-benzoyl-3-carboxy-4-methylpyrrole-2-acetic acid, as whitecrystals, m.p. 250-253° C.

(C) Ethyl 5-benzoyl-3-carboxy-4-methylpyrrole-2-acetate

A solution of 8.0 g. (0.028 mole) of5-benzoyl-3-carboxy-4-methylpyrrole-2-acetic acid in 80 ml. of 0.5%ethanolic hydrogen chloride is refluxed for 90 minutes. The solution ischarcoaled, filtered, and the filtrate evaporated in vacuo to yield acrystalline residue which is recrystallized from acetone to give ethyl5-benzoyl-3-carboxy-4-methylpyrrole-2-acetate, m.p. 183-185° C.

(E) 5-Benzoyl-4-methylpyrrole-2-acetic acid

A solution of 4.13 g. (0.0131 mole) of ethyl5-benzoyl-3-carboxy-4-methyl-pyrrole-2-acetate in 80 ml. of quinoline inthe presence of a trace amount of copper chromite is heated at 180-183°C. for 5 hours. The mixture is poured into dilute hydrochloric acid andextracted three times with ether. The ether extracts are combined andwashed successively with dilute hydrochloric acid, sodium bicarbonatesolution and brine and then dried over anhydrous magnesium sulfate. Thesolvent is evaporated in vacuo to give about 4 g. of semisolid ethyl5-benzoyl-4-methylpyrrole-2-acetate which is used in the followinghydrolysis procedure without further purification. The entire semisolidis dissolved in 20 ml. of ethanol and 20 ml. of 1N sodium hydroxidesolution is added. The mixture is heated under reflux for 30 minutes.The solvent is then evaporated in vacuo, and the residue dissolved inwater and washed with ether. The aqueous solution is acidified withdilute hydrochloric acid and the resulting crystalline solid (1.6 g.,50% yield) is collected by filtration and air-dried. The product,5-benzoyl-4-methylpyrrole-2-acetic acid is recrystallized three timesfrom acetone-water with charcoaling, m.p. 167-168° C.

(F) BOC-5-benzoyl-4-methylpyrrole-2-acetic acid

The procedure of Example 1, part C is repeated using5-benzoyl-4-methylpyrrole-2-acetic acid to giveBOC-5-benzoyl-4-methylpyrrole-2-acetic acid.

(G) BOC 4-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33C is repeated usingBOC-5-benzoyl-4-methylpyrrole-2-acetic acid to give BOC4-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(H) 4-Methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using BOC4-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to give4-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H, R₂=H, R₃ =phenyl, R₄ =H, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 634-Methyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-(p-Chlorophenyl)-1,2,3-butanetrione-2-oxime

The procedure described by Ceresole in Ber., 17, 815 (1884), wherein1-aryl-1,3-butanedion is reacted with nitrous acid to yield thecorresponding 1-aryl-1,2,3-butanetrione-2-oxime, is followed to prepare1-(p-chlorophenyl)-1,2,3-butanetrione-2-oxime.

(B) Ethyl-5-(p-chlorobenzyl)-3-ethoxycarbonyl-4-methyl-pyrrole-2-acetate

By repeating the procedure of Example 62, part B with an equivalentamount of 1-(p-chlorophenyl)-1,2,3-butanetrione-2-oxime,ethyl-5-(p-chlorobenzyl)-3-ethoxycarbonyl-4-methylpyrrole-2-acetate isobtained.

(C) 5-(p-Chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-acetic acid

The hydrolysis procedure of Example 62, part C is repeated, except thatan equivalent amount of the ester obtained in part B of this Example isused to yield 5-(p-chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-aceticacid.

(D) Ethyl 5-(p-chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-acetate

The partial reesterification procedure in Example 62 D above is repeatedusing an equivalent amount of the acid obtained in part C of thisExample to yield ethyl5-(p-chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-acetate.

(E) 5-(p-Chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-acetic acid

The procedure of Example 62, part E is repeated using an equivalentamount of the ester obtained in part D of this Example to yield5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid.

(F) BOC 5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid

The procedure of Example 33C is repeated using5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid to give BOC5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid.

(G) BOC 4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3oxapentalen-2-one

BOC 5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce BOC4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(H) 4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3oxapentalen-2-one

The procedure of Example 33E is repeated using BOC4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-oneto produce4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-chlorophenyl, R₄ =H, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 644-Methyl-5-(4'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-(p-Methylphenyl)-1,2,3-butanetrione-2-oxime

The procedure described by Ceresole in Ber., 17, 815 (1884), wherein1-aryl-1,3-butanediones are reacted with nitrous acid to yield thecorresponding 1-aryl-1,2,3-butanetrione-2-oximes, is followed to prepare1-(p-methylphenyl)-1,2,3-butanetrione-2-oxime.

(B) Ethyl 5-(p-methylbenzoyl)-3-ethoxycarbonyl-4-methylpyrrole-2-acetate

By repeating the procedure of Example 62, part B with an equivalentamount of 1-(p-methylphenyl)-1,2,3-butanetrione-2-oxime, ethyl5-(p-methylbenzoyl)-3-ethoxycarbonyl-4-methylpyrrole-2-acetate isobtained.

(C) Ethyl-5-(p-methylbenzoyl)-3-carboxy-4-methylpyrrole-2-acetic acid

The hydrolysis procedure of Example 62, part C is repeated, except thatan equivalent amount of the ester obtained in part B of this Example isused to yield ethyl5-(p-methylbenzoyl)-3-carboxy-4-methylpyrrole-2-acetic acid.

(D) Ethyl 5-(p-methylbenzoyl)-3-carboxy-4-methylpyrrole-2-acetate

The partial reesterification procedure in Example 62 D above is repeatedusing an equivalent amount of the acid obtained in part C of thisExample to yield ethyl5-(p-methylbenzoyl)-3-carboxy-4-methylpyrrole-2-acetate.

(E) 5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid

The procedure of Example 62, part E is repeated using an equivalentamount of the ester obtained in part D of this Example to yield5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid.

(F) BOC 5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid

The procedure of Example 33C is repeated using5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid to produce BOC5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid.

(G) BOC4-Methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

BOC 5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce BOC4-methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.

(G)4-Methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using BOC4-methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-oneto give4-methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R.sub.1 =H, R₂ =H, R₃ =4'-methylphenyl, R₄ =H, R₅ =methyl, Y=CO, m=1,n=0).

EXAMPLE 654-Methyl-5-(4'-Methoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-(p-Methoxyphenyl)-1,2,3-butanetrione-2-oxime

The procedure described by Ceresole in Ber., 17, 815 (1884), wherein1-aryl-1,3-butanediones are reacted with nitrous acid to yield thecorresponding 1-aryl-1,2,3-butanetrione-2-oximes, is followed to prepare1-(p-methoxyphenyl)-1,2,3-butanetrione-2-oxime.

(B) Ethyl5-(p-methoxybenzoyl)-3-ethoxycarbonyl-4-methylpyrrole-2-acetate

By repeating the procedure of Example 62, part B with an equivalentamount of 1-(p-methoxyphenyl)-1,2,3-butanetrione-2-oxime, ethyl5-(p-methoxybenzoyl)-3-ethoxycarbonyl-4-methylpyrrole-2-acetate isobtained.

(C) Ethyl 5-(p-methoybenzoyl)-3-carboxy-4-methylpyrrole-2-acetate

The hydrolysis procedure of Example 62, part C is repeated, except thatan equivalent amount of the ester obtained in part B of this Example isused to yield ethyl5-(p-methoxybenzoyl)-3-carboxy-4-methylpyrrole-2-acetate.

(D) Ethyl 5-(p-methoxybenzoyl)-3-carboxy-4-methylpyrrole-2-acetate.

The partial reesterification procedure in Example 62 D above is repeatedusing an equivalent amount of the acid obtained in part C of thisExample to yield ethyl5-(p-methoxybenzoyl)-3-carboxy-4-methylpyrrole-2-acetate.

(E) 5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid

The procedure of Example 62, part E is repeated using an equivalentamount of the ester obtained in part D of this Example to yield5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid.

(F) BOC 5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid

The procedure of Example 33C is repeated using5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid to produce BOC5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid.

(G) BOC4-methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

BOC 5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce BOC4-methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

(H)4-Methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The procedure of Example 33E is repeated using BOC4-methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-oneto give4-methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-methoxyphenyl, R₄ =H, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 666-Benzyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 2-Dimethylaminomethyl-1-benzylpyrrole

A solution of 8.2 g. (0.1 mole) dimethylamine hydrochloride in 8 ml.formalin is added dropwise to 17.12 g. (0.1 mole) of 1-benzylpyrrole.The mixture is stirred at room temperature until solution occurs (about4 hours). The solution is poured into 10% sodium hydroxide solution andthen extracted into ether three times. The combined organic fractionsare washed with a saturated solution of sodium chloride, dried overmagnesium sulfate and the solvent evaporated in vacuo. The product,2-dimethylaminomethyl-1-benzylpyrrole, is distilled at reduced pressure,b.p. 73° C., 0.025 mm. Hg.

(B) 2-Dimethylaminomethyl-1-benzylpyrrole methiodide

A solution of 100 g. (0.47 mole) of2-dimethylaminomethyl-1-benzylpyrrole in 200 ml. of absolute ethanol iscooled to 5° C. To this is added dropwise 29.4 ml. (0.47 mole) of methyliodide. A white solid precipitates. The suspension is stirred until theprecipitate is so thick that additional stirring becomes impossible. Thesolid, 2-dimethylaminomethyl-1-benzylpyrrole methiodide, is filtered offand dried in vacuum.

(C) 1-Benzylpyrrole-2-acetonitrile

A suspension of 88.9 g. (0.25 mole) of2-dimethylaminomethyl-1-benzylpyrrole methiodide is added to asuspension of 12.8 g. (0.26 mole) of sodium cyanide in 40 ml.dimethylsulfoxide. The mixture is heated under reflux for 3 hours, andstirring at room temperature is continued overnight. The reactionmixture is poured into water and extracted three times with ether. Thecombined ether extracts are washed with brine and dried over anhydrousmagnesium sulfate. The ether solvent is evaporated in vacuo to give anoily residue which crystallizes upon standing. Recrystallization frommethylcyclohexane yields the product, 1-benzylpyrrole-2-acetonitrile,m.p. 62-63° C.

(D) 1-Benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile

A solution of 8.43 ml. (0.067 mole) of p-chlorobenzoyl chloride and 8.8g. (0.067 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane isadded to a solution of 13.0 g. (0.067 mole) of1-benzylpyrrole-2acetonitrile in 50 ml. of 1,2-dichloroethane at 5° C.over a 5 minute period. The reaction mixture is stirred for 15 minutesand then heated quickly to reflux for 3 minutes. The mixture is pouredinto ice-hydrochloric acid and then filtered. The aqueous layer isseparated and washed with chloroform. The combined organic fractions arewashed successively with N,N-dimetylaminopropylamine solution, dilutehydrochloric acid and brine and then dried over anhydrous magnesiumsulfate. The solvent is evaporated to yield an oily residue from whichthe desired compound is isolated by column chromatography on neutralalumina with a 50--50 mixture of benzene ether as the eluting solvent.Evaporation of the elute affords1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile as a yellow solidwhich is recrystallized from methanol, m.p. 106-108° C.

(E) 1-Benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid

The nitrile-to-acid transformation procedure of Example 49B is followedusing an equivalent amount of the acetonitrile obtained in Part D ofthis example to yield 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-aceticacid.

(F)6-Benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, Part C to produce6-benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-chlorophenyl, R₄ =phenyl, R₅ =H, Y=CO, X=CH₂, m=1,n=1).

EXAMPLE 676-Methyl-5-(4'-Isopropylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(p-Isopropylbenzoyl)-1-methylpyrrole-2-acetonitrile

To a suspension of 17.5 g. (0.131 mole) aluminum chloride in 60 ml.1,2-dichloroethane is added 24 g (0.131 mole) p-isopropylbenzoylchloride. The resulting mixture is added slowly and dropwise to achilled solution (0° C.) of 15.7 g. (0.131 mole)1-methylpyrrole-2-acetonitrile in 100 ml. of 1,2-dichloroethane. Afterthe addition is complete, the mixture is stirred at room temperature fortwenty minutes and heated at reflux for three minutes. The reactionmixture is then cooled and poured into ice-dilute hydrochloric acid. Theorganic phase is separated and washed successively withN,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and asaturated solution of sodium chloride; dried over magnesium sulfate; andthe solvent evaporated. The product,5-(p-isopropylbenzyl)-1-methylpyrrole-2-acetonitrile, is isolated fromthe residual oil by column chromatography. The column is packed withacid washed alumina and eluted with benzene, ether and ethylacetate. Theproduct is found in the first compound-bearing fraction which absorbsultraviolet light at approximately 250 mμ. It is purified byrecrystallization twice in ether: pentane. m.p. 59-64° C. Anal. Calcd.for C₁₇ H₁₈ N₂ O: N, 10.53%. Found: N,10.71%.

(B) 5-(p-isopropylbenzoyl)-1-methylpyrrole-2-acetic acid

A solution of 6.5 g. (0.024 mole) of5-(p-isopropylbenzoyl)-1-methylpyrrole-2-acetonitrile, 52 ml. 1N sodiumhydroxide and 50 ml. 95% ethanol are heated at reflux overnight. Theethanol is then evaporated, and the remaining yellow solution is pouredinto ice-dilute hydrochloric acid. A precipitate forms which isseparated by filtration and recrystallized in ether: hexane. The solidis then partitioned between sodium bicarbonate solution and ether. Thesodium bicarbonate phase is separated and acidified with dilutehydrochloric acid. The white precipitate,5-(p-isopropylbenzoyl)-methylpyrrole-2-acetic acid, is filtered anddried in vacuo, m.p. 98-101° C. Anal. Calcd. for C₁₇ H₁₉ NO₃ : N, 4.91%.Found: N, 5.14%.

(C)6-Methyl-5-(4'-isopropylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Isopropylbenzoyl)-1-methylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(4'-isopropylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-isopropylphenyl, R₄ =methyl, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 686-Methyl-5-(2'-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-methyl-5-(o-toluoyl)-pyrrole-2-acetonitrile

To a solution of 24 g. (0.20 mole) of 1-methylpyrrole-2-acetonitrile and30.92 g. (0.20 mole) o-toluoyl chloride in 200 ml. methylene chloride(cooled externally to -20° C.) is added dropwise 23.4 ml. (0.20 mole) ofstannic chloride. After the addition is complete, the yellow mixture ispermitted to come to room temperature. The mixture is then poured intoice-dilute hydrochloric acid. The two phases are separated. The organicphase is washed consecutively with N,N-dimethyl-1,3-propanediamine, 3Nhydrochloric acid, and saturated sodium chloride solution; dried overmagnesium sulfate; and the product,1-methyl-5-(o-toluoyl)-pyrrole-2-acetonitrile, is separated from theresidual oil by chromatography. The column is packed with acid washedalumina in hexane. The eluant is benzene. The product is found in thefirst compound bearing fraction as determined by ultraviolet absorptionat 260 mμ. The benzene is evaporated and the resultant solid is purifiedby recrystallization twice from methanol, m.p. 90-92.5° C.

(B) 1-methyl-5-(o-toluoyl)-pyrrole-2-acetic acid

A solution of 10.6 g. (0.0445 mole) of1-methyl-5-(o-toluoyl)-pyrrole-2-acetonitrile, 89 ml. 1N sodiumhydroxide and 10 ml. 95% ethanol is heated at reflux for 18 hours,cooled and poured into dilute hydrochloric acid, and extracted withchloroform. The chloroform phase is separated and extracted with sodiumbicarbonate solution. The product,1-methyl-5-(o-toluoyl)-pyrrole-2-acetic acid, is precipitated from theaqueous phase upon treatment with 3N hydrochloric acid, separated byfiltration, and purified by recrystallization in isopropanol usingcharcoal while the solution is still warm, and subsequentrecrystallization with methanol, m.p. 133-135° C. Anal. Calcd. for C₁₅H₁₅ NO₃ : C, 70.02; H, 5.88; N, 5.44%. Found: C, 70.07; H, 5.97; N,5.54%.

(C) 6-Methyl-5-(2'-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Methyl-5-(o-toluoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(2'-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H,R₂ =H, R₃ =2'-methylphenyl, R₄ =methyl, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 696-Methyl-5-(2'-Thienoyl)-α-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-Methyl-5-(2'-thienoyl)-pyrrole-2-acetonitrile

A solution of 20.0 g. (0.15 mole) of aluminum chloride and 22.0 g. (0.15mole) of thiophene-2-carboxylic acid chloride in 200 ml.1,2-dichloroethane is added to a solution of 18.0 g. (0.15 mole) of1-methyl-pyrrole-2-acetonitrile in 100 ml. of 1,2-dichloroethane at 5°C. over a period of 5 minutes. The mixture is stirred for 20 min. andthen quickly heated to reflux for 3 minutes. It is poured intoice-hydrochloric acid. The organic layer is separated and the aqueoussolution washed with 1,2-dichloroethane. The combined organic solutionsare washed consecutively with water, N,N-dimethylaminopropylamine,dilute hydrochloric acid and brine. The solution is then dried overmagnesium sulfate and the solvent evaporated in vacuo. The residuecrystallizes to give a yellow solid which shows two spots on thin layerchromatography (1:1 ethyl acetate, cyclohexane on silica gel). The solidis dissolved in benzene and seeded with crystals of1-methyl-5-(2'-thienoyl)-pyrrole-2-acetonitrile obtained by exhaustivecrystallization from benzene. After crystallization, the supernatantliquid is decanted from the precipitated1-methyl-5-(2'-thienoyl)-2-acetonitrile and evaporated. Thethus-obtained solid is recrystallized from methanol and seeded withcrystals of 1-methyl-5-(2'-thienoyl)-pyrrole-2-acetonitrile which wereobtained by exhaustive crystallization of a another run from methanol.The mother liquor from the crystallization of the latter compound isevaporated and recycled through the same crystallization processes.After four cycles, there is obtained1-methyl-5-(2'-thienoyl)-pyrrole-2-acetonitrile, m.p. 132-133° C.

(B) 1-Methyl-5-(2'-thienoyl)-pyrrole-2-acetic acid

A suspension of 7.35 g. (0.032 mole) of1-methyl-5-(2'-thienoyl)-pyrrole-2-acetonitrile in 30 ml. of 95% ethanoland 64 ml. (0.064 mole) of 1N sodium hydroxide solution is refluxed for5 hours. The mixture is cooled, and the ethanol evaporated in vacuo.Water is added, and the solution is washed successively with methylenechloride and ether and clarified with charcoal. The solution isacidified with dilute hydrochloric acid and the precipitated solid,1-methyl-5-(2'-thienoyl)-pyrrole-2-acetic acid, is collected and driedin vacuo, m.p. 140-142° C. It is recrystallized from methanol-water togive the product as a white solid, m.p. 141-142° C. Anal. Calcd, for C₁₂H₁₁ NO₃ S: C, 57.83; H, 4.45; H 5.62%. Found: C, 57.81; H, 4.44; N5.68%.

(C) 6-Methyl-5-(2'-thienoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Methyl-5-(2'-thienoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce6-methyl-5-(2'-thienoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁=H, R₂ =H, R₃ =2'-thiophenyl, R₄ =methyl, R₅ =H, Y=CO, m=1, n=0).

EXAMPLE 706-Methyl-5-(5'-Methyl-2'-Thienoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-Methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetonitrile

To a suspension of 25.54 g. (0.019 mole) anhydrous aluminum chloride in70 ml. of 1,2-dichloroethane is added 30.7 g. (0.019 mole)5-methyl-2-thienoyl chloride. The resulting solution is added dropwiseto a chilled (0° C.) solution of 24 g. (0.02 mole)1-methylpyrrole-2-acetonitrile. After the addition, the solution isstirred at room temperature for approximately 40 minutes, and thenheated at reflux for 3 minutes and poured onto ice acidified with dilutehydrochloric acid. The two phases are separated. The organic phase iswashed successively with N,N-dimethyl-1,3-propanediamine, 3Nhydrochloric acid and saturated sodium chloride solution. It is thendried over magnesium sulfate and the solvent evaporated. The resultingsolid, 1-methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetonitrile, isseparated by filtration and purified by washing in cold methanol andbenzene, m.p. 118-121° C.

(B) 1-Methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetic acid

A solution of 10.5 g. (0.043 mole) of1-methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetonitrile, 86 ml. 1Nsodium hydroxide and 50 ml. 95% ethanol is refluxed for 15 hours andthen cooled and poured into 3N hydrochloric acid. The white precipitate,1-methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetic acid, is collectedby filtration, air dried, and recrystallized twice in acetonitrile, m.p.152-154° C. Anal. Calcd. for C₁₃ H₁₃ NO₃ S: C, 59.37; H, 4.98; N, 5.33.Found: C, 59.15; H, 4.99; N, 5.64.

(C)6-Methyl-5-(5'-methyl-2'-thienoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce6-methyl-5-(5'methyl-2'-thienoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =5'-methyl-2'-thiophenyl, R₄ =methyl, R₅ =H, Y=CO,m=1, n=0).

EXAMPLE 716-Methyl-5-(p-Trifluoromethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetonitrile

A solution of 14.4 g. (0.12 mole) of 1-methylpyrrole-2-acetonitrile and25 g. (0.12 mole) of p-trifluoromethylbenzoyl chloride in 120 ml.methylene chloride is chilled to -25° C. (external bath). Then 14 ml.(0.12 mole) stannic chloride is added dropwise over a half hour. Theresultant suspension is permitted to come to room temperature and pouredinto ice-dilute hydrochloric acid. The aqueous phase is separated andwashed successively with N,N-dimethyl-1,3-propane-diamine, 3Nhydrochloric acid and a saturated solution of sodium chloride. Thesolvent is evaporated, and the product is isolated from the residual oilby column chromatography using acid-washed alumina. The solvents hexane,benzene, and ether are used as eluents. The first compound-bearingfraction not giving a positive Enrlich's test (in benzene) is collected.The solvent is evaporated and the resultant solid,1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetonitrile, inpurified by recrystallization from isopropanol, m.p. 95-97.5° C.

(B) 1-Methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetic acid

A solution of 2.2 g. (0.0075 mole) of1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetonitrile, 15 ml. 95%ethanol and 15 ml. 1N sodium hydroxide is refluxed for 18 hours. Theethanol is evaporated. The resultant yellow solid is dissolved withwater and poured into dilute hydrochloric acid. The resultant whiteprecipitate 1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetic acid,is collected by filtration and purified by recrystallization fromisopropanol, m.p. 152-154° C. Anal. Calcd. for C₁₅ H₁₂ F₃ NO₃ : C,57.88; H, 3.89; N, 4.50%. Found: C, 57.92; H, 4.12; N, 4.38%.

(C)6-Methyl-5-(p-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1-Methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to produce6-methyl-5-(p-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-trifluoromethylphenyl, R₄ =methyl, R₅ =H, Y=CO,m=1, n=0).

EXAMPLE 724,6-Dimethyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate

To a solution of 500 ml. of 25% aqueous methylamine is added 93 g. (0.46mole) of diethyl acetone-dicarboxylate. To the mixture is added 72 g.(0.782 mole) of chloroacetone over a 10-minute period. The temperatureis kept below 60° C. by external cooling. After 2 hours, the mixture ispoured into ice-hydrochloric acid. The solid is collected by filtration,washed with water and air dried. It is recrystallized from hexane togive ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate as a whitesolid, m.p. 71-72° C. Anal. Calcd. for C₁₃ H₁₉ NO₄ : C, 61.64; H, 7.56;N, 5.53%. Found: C, 61.64; H, 7.64; N, 5.71%.

(B) Ethyl 5-(p-chlorobenzoyl)-1,4dimethyl-3-ethoxycarbonylpyrrole-2-acetate

A solution of 17.5 g. (0.1 mole) p-chlorobenzoyl chloride and 13.3 g.(0.1 mole) aluminum chloride in 150 ml. of dichloroethane is addedrapidly to a solution of 25.3 g. (0.1 mole) of ethyl1,4-dimethyl-3ethoxycarbonylpyrrole-2-acetate in 100 ml. of refluxing1,2-dichloroethane. The solution is refluxed for 3.5 hours and pouredinto ice-hydrochloric acid. The organic layer is separated, and theaqueous layer washed with 1,2-dichloroethane. The combined organics arewashed successively with water, N,N-dimethylaminopropylamine, dilute HCland brine. The solution is then dried over anhydrous magnesium sulfateand the solvent evaporated in vacuo. The residue product is crystallizedfrom cyclohexane and recrystallized from methanol to give ethyl5-(p-chlorobenzoyl)-1,4 dimethyl-3-ethoxycarbonylpyrrole-2-acetate as awhite solid, m.p. 91-93° C.

(C) 5-(p-Chlorobenzoyl)-3-carboxy-1,4-dimethylpyrrole-2-acetic acid

A suspension of 17.3 g. (0.0435 mole) of ethyl 5-(p-chlorobenzoyl)-1,4dimethyl-3-ethoxypyrrole-2-acetate in 170 g. of 25% sodium hydroxide isheated under reflux for 3 hours. The suspension is poured into ice, andthe resulting yellow solution is added to ice-hydrochloric acid withstirring. The precipitated solid is collected by filtration, air driedand recrystallized from acetone containing 10% water to give5-(p-chlorobenzoyl)-3-carboxy-1,4-dimethylpyrrole-2-acetic acid as awhite solid, m.p. 253-254° C.

(D) Ethyl 5-(p-chlorobenzoyl)-3-carboxy-1,4-dimethylpyrrole-2-acetate

A suspension of 2.0 g. of5-(p-chlorobenzoyl)-3-carboxy-1,4-dimethylpyrrole-2-acetic acid in 20ml. of 0.5% ethanolic hydrogen chloride is heated under reflux. Thesolid gradually dissolves. After 40 minutes, a white crystalline solidprecipitates. The solution is cooled, and the solid product, ethyl5-(p-chlorobenzyl)-3-carboxy-1,4-dimethylpyrrole-2-acetate, is filteredand dried, m.p. 197-198° C.

(E) Ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate

A 9.0 g. (0.0255 mole) sample of ethyl5-(p-chlorobenzoyl)-3-carboxy-1,4-dimethylpyrrole-2-acetate is heatedunder nitrogen at 210 to 230° C. for 2 hours. Gas evolves. The residueis molecularly distilled in a sublimator at 195° C., 0.05 mm/Hg. Thesublimate is recrystallized from cyclohexane to give ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate as a white solid, m.p.107-109° C.

(F) 5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid

A suspension of 4.0 g. (0.0125 mole) of ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate in 26 ml. of 0.5 Nsodium hydroxide (0.013 mole) is heated under reflux for 30 minutes. Theresulting solutions is acidified with dilute hydrochloric acid, and theprecipitated solid is collected by filtration, air dried andrecrystallized from 2-propanol to give5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid as a whitecrystalline solid, m.p. 178-179° C. Anal. Calcd. for C₁₅ H₁₄ ClNO₃ : C,61.76; H, 4.83; N, 4.82%. Found: C, 61.68; H, 4.96; N, 4.89%.

(G)4,6-Dimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce4,6-dimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-chlorophenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1,n=0).

EXAMPLE 734,6-Dimethyl-5-(p-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 1,4-dimethyl-3-ethoxycarbonyl-5(p-toluoyl)-pyrrole-2-acetate

A solution of 30.8 g. p-toluoyl chloride and 26.6 g. (0.2 mole) ofaluminum chloride in 250 ml. of 1,2-dichloroethane is added to arefluxing solution of 50.6 g. (0.2 mole) of ethyl3-ethoxycarbonyl-1,4-dimethylpyrrole-2-acetate in 250 ml. of1,2-dichloroethane over 30 minutes. The mixture is heated under refluxfor 90 minutes, and poured into ice-diluted hydrochloric acid. Theorganic solution is separated, washed with brine, and dried overmagnesium sulfate. The solvent is evaporated in vacuo, and the residueis recrystallized from methanol to give ethyl1,4-dimethyl-3-ethoxycarbonyl-5-(p-toluoyl)-pyrrole-2-acetate as a whitesolid, m.p. 108-111° C.

(B) 3-Carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid

A suspension of 54 g. (0.145 mole) of ethyl1,4-dimethyl-3-ethoxycarbonyl-5-(p-toluoyl)-pyrrole-2-acetate in 500 g.of 25% sodium hydroxide is heated at just below reflux for 3 hours. Theyellow suspension is then poured into ice-hydrochloric acid, and theprecipitated solid is collected, air dried and recrystallized fromacetone-water to give3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid as a whitesolid, m.p. 229-230° C. Anal. Calcd. for C₁₇ H₁₇ NO₅ : C, 64.75; H,5.43; N, 4.44%. Found: C, 64.86; H, 5.53; N, 4.47%.

(C) Ethyl 3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate

A solution of 37 g. (0.118 mole) of3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid in 370 ml. ofethanol containing 1.8 g. of dry hydrogen chloride is heated underreflux for 45 minutes. The solution is cooled, and the solid whichprecipitated, ethyl3-carboxy-1,4-dimethyl-5-(o-toluoyl)-pyrrole-2-acetate, is collected,m.p. 200-202° C.

(D) Ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate

A solution of 33.0 g. (0.096 mole) of ethyl3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate in 200 ml. ofquinoline with 0.1 g. copper chromite added is heated under nitrogen for6 hours at 200° C., then for 30 minutes at 220° C. The quinoline isdistilled off in vacuo. The residue is dissolved in ether and washedsuccessively with dilute hydrochloric acid, dilute sodium hydroxide, andbrine; dried over magnesium sulfate; and the solvent evaporated in vacuoto give a brown oily residue which crystallizes. It is recrystallizedfrom methanol, sublimed at 150° C. (0.025 mm/Hg) and recrystallized fromhexane to give ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate as awhite solid, m.p. 90-93° C.

(E) 1,4-Dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid

A suspension of 8.5 g. (0.0284 mole) of ethyl1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate in 29 ml. of 1N sodiumhydroxide solution is heated under reflux for 20 minutes. The yellowsolution is diluted with water and added to dilute hydrochloric acid.The precipitated solid is collected, dried in vacuo, and recrystallizedfrom 2-propanol to give 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acidas a white solid, m.p. 160-161° C. Anal. Calcd. for C₁₆ H₁₇ NO₃ : C,70.83; H, 6.32; N, 5.16%. Found: C, 70.90; H, 6.39; N, 5.25%.

(F) 4,6-Dimethyl-5-(p-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one1,4-Dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce4,6-dimethyl-5-(p-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁=H, R₂ =H, R₃ =4'-methylphenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 744,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-Benzoyl-1,4-dimethylpyrrole-2-acetic acid

By following the procedure outlined in Example 72B-F, except that anequivalent quantity of benzoyl chloride is employed as the startingacylating agent in place of the p-chlorobenzoyl chloride used in Example72B, there is obtained 5-benzoyl-1,4-dimethylpyrrole-2-acetic acid.

(B) 4,6-Dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-Benzoyl-1,4-dimethylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H,R₂ =H, R₃ =phenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 754,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-acetic acid

By following the procedure outlined in Example 72B-F, except that anequivalent quantity of 2,3,5-tribromobenzoyl chloride is employed as thestarting acylating agent in place of the p-chlorobenzoyl chloride usedin Example 72B, there is obtained5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetic acid.

(B)4,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to produce4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =2',3',5'-tribromophenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 764-Ethyl-6-Methyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 1--Chloro-2-butanone

Chlorination of methylethylketone is carried out according to Bruylantand Houssiau [Bull. Soc. Chem. Belg., 6, 492 (1952)]. The mixtureobtained is fractionally distilled at atmospheric pressure through aVigreaux column. The fraction boiling at 135-144° C. is shown by vaporphase chromatography to contain approximately 75% 1-chloro-2-butanoneand 25% 3-chloro-2-butanone. This fraction may be used in the next stepwithout further separation.

(B) Ethyl 3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate

A 900 ml. solution of 25% aqueous methylamine is cooled in an ice bathand 101 g. (0.5 mole) of diethyl acetone decarboxylate is added. To themixture is added 110 g. of the 1-chloro-2-butanone obtained in part A.Intermittant cooling is applied to keep the temperature below 60° C. Themixture is stirred for one hour and poured into ice-hydrochloric acid.The crystalline product is collected by filtration and recrystallizedfrom methanol to yield ethyl3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate as in a white solid,m.p. 65-67° C.

(C) Ethyl(5-p-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate

A solution of 13.8 g. (0.0788 mole) of p-chlorobenzoyl chloride and 10.5g. (0.0788 mole) of aluminum chloride in 120 ml. of 1,2-dichloroethaneis added to a refluxing solution of 21.8 g. (0.0788 mole) of ethyl3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate. The mixture isheated under reflux for 10 hours and stirred at room temperature for anadditional 10 hours. It is then poured into ice-hydrochloric acid. Theorganic layer is separated, and the aqueous layer washed with1,2-dichloroethane. The combined organics are washed successively withwater, N,N-dimethylaminopropylamine, dilute HCl and brine. The solutionis then dried over anhydrous magnesium sulfate and the solventevaporated in vacuo. The residual red oily residue crystallizes onstanding. It is recrystallized twice from methanol to give ethyl(5-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methyl-pyrrole-2-acetate asa white solid, m.p. 72-74° C.

(D) 3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid

A suspension of 18.2 g. (0.044 mole) of ethyl5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetatein 170 ml. of 25% aqueous sodium hydroxide solution is heated underreflux for 3 hours. It is cooled, diluted with water and acidified withdilute hydrochloric acid. The precipitated solid is collected byfiltration and air dried. It is recrystallized from acetone-water togive 3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetateacid, m.p. 211-212.5° C.

(E) Ethyl3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate

A solution of 13.8 g. (0.0375 mole) of3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid in140 ml. of 0.5% ethanolic hydrogen chloride is heated under reflux for45 minutes. After cooling, the precipitated solid is collected. A secondcrop is obtained by partial evaporation of the solvent, recrystallizedfrom ethanol and combined with the first crop to give ethyl3-carboxy-5-(γ-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate, m.p.184-186° C.

(F) Ethyl 5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate

A 13.7 g. (0.035 mole) sample of ethyl3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methypyrrole-2-acetate is heatedat 200° C. to 210° C. under nitrogen for 90 minutes. The resulting oilis molecularly distilled at 185° C. and 0.1 mm pressure to yield a solidwhich is recrystallized from cyclohexane and then methanol to give ethyl5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate as a white solid,m.p. 73-75° C.

(G) 5-(p-Chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid

A suspension of 4.5 g. (0.0136 mole) of ethyl5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate in 28 ml. 0.5 Nsodium hydroxide and 1 ml. of ethanol is heated under reflux for 30minutes. The mixture is then poured into ice-dilute hydrochloric acid.The precipitated solid is filtered, air dried and recrystallized from2-propanol to give 5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-aceticacid as a white solid, m.p. 129-131° C. Anal. Calcd. for C₁₆ H₁₆ ClNO₃ :C, 62.85; H, 5.29; N, 4.5%. Found: C, 62.58; H, 5.40; N, 4.83%.

(H)4-Ethyl-6-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, Part C to produce4-ethyl-6-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-chlorophenyl, R₄ =ethyl, methyl, Y=CO, m=1, n=0).

EXAMPLE 77Rac-1,4,6-Trimethyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetate

6.4 grams (0.02 mole) of ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate is dissolved in 100ml. of dimethyl sulfoxide (DMSO) and added to a slurry of 0.48 g. (0.02mole) of sodium hydride in approximately 30 ml. of DMSO. The mixture isstirred for 30 minutes before 2.84 g. (0.02 mole) of methyl iodide isadded. Stirring is continued for 15 minutes. The reaction mixture isthen poured into water, and the precipitate filtered off andrecrystallized from 2-propanol to yield ethyl5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetate, m.p. 88-90° C.

(B) 5-(p-Chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid

An ethanol solution of 2.9 g. (0.0087 mole) of ethyl5-(p-chlorobenzoyl)1,4,α-trimethylpyrrole-2-acetate is added to 17.5 ml.0.5 N sodium hydroxide solution, and the mixture is heated under refluxfor one hour. The ethanol is evaporated in vacuo, and the solutionpoured into dilute hydrochloric acid. The precipitated solid iscollected by filtration and recrystallized from ether-cyclohexane togive 5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid as a whitesolid, m.p. 153-154° C. Anal. Calcd. for C₁₆ H₁₆ ClNO₃ : C, 62.85; H,5.29; N, 4.58%. Found: C, 62.74; H, 5.22; N, 4.47%.

(C)Rac-1,4,6-trimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-1,4-trimethyl-pyrrole-2-acetic acid is subjected tothe procedure of Example 1, Part C to producerac-1,4,6-trimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-chlorophenyl, R₄ methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 78Rac-1,4,6-Trimethyl-5-(4'-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 1,4,α-trimethyl-5-(p-toluoyl)-pyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of the ester obtained from Examples 73D ismethylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl 1,4,α-trimethyl-5-(p-toluoyl)-pyrrole-2-acetate.

(B) 1,4,α-trimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theα-methyl ester obtained in part A of this Example to yield1,4,α-trimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(4'-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The acid from Example 78B is subjected to the procedure of Example 1,part C to producerac-1,4,6-trimethyl-5-(4'-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-methylphenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 79Rac-1,4,6-Trimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 1,4,α-trimethyl-5-benzoyl-pyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of the ester obtained from Example 74A is methylatedinstead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetateused in Example 77A, to yield ethyl1,4,α-trimethyl-5-benzoyl-pyrrole-2-acetate.

(B) 1,4,α-trimethyl-5-benzoyl-pyrrole-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theα-methyl ester obtained in part A of this Example to yield1,4,α-trimethyl-5-benzoyl-pyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The acid from Example 79B is subjected to the procedure of Example 1,part C to producerac-1,4,6-trimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =phenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 804-Ethyl-1,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 4-ethyl-1,α-dimethyl-5-benzoyl-pyrrole-2-acetate

The methylation procedure of Example 78A is repeated, except that anequivalent quantity of the ester obtained from Examples 73D, 74A and 76Fis methylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl 4-ethyl-1,α-dimethyl-5-benzoyl-pyrrole-2-acetate

(B) 4-Ethyl-1,α-dimethyl-5-benzoyl-pyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theα-methyl ester obtained in part A of this Example to yield4-ethyl-1,α-dimethyl-5-benzoyl-pyrrole-2-acetic acid.

(C)Rac-4-ethyl-1,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

The acid from Example 80B is subjected to the procedure of Example 1,part C to producerac-4-ethyl-1,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.(R₁ =methyl, R₂ =H, R₃ =phenyl, R₄ =methyl, R₅ =ethyl, Y=CO, m=1, n=0).

EXAMPLE 811,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxa-Pentalen-2-OneSynthesized with (-) Acid

(A) (-)-5-(p-Chlorobenzoyl)-1,α-dimethylpyrrole-2-acetic acid

A solution of 16.5 g. (0.057 mole) of racemic5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid and 6.8 g.(0.057 mole) of (+)-α-methylbenzylamine in 95% ethanol deposits crystalson standing. The solid is collected and recrystallized twice from2-propanol to give 4.4 g. of salt, m.p. 181-182° C., the mother liquorsbeing set aside for use as shown in Example 82. The salt is partitionedbetween ether and 3N hydrochloric acid. The ether layer is washed withdilute hydrochloric acid and brine and dried over magnesium sulfate. Thesolvent is evaporated in vacuo. The solid residue is dissolved in hotether and methylcyclohexane is added. The ether is allowed to evaporateand the precipitated solid,(-)-5-(p-chlorobenzoyl)-1,α-dimethylpyrrole-2-acetic acid, is collectedby filtration: (13% yield), m.p. 106-107° C.

(B)1,6-Dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-pentalen-2-onesynthesized with (-) acid

The acid from Example 81A is subjected to the procedure of Example 1,part C to produce1,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-pentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-chlorophenyl, R₄ =methyl, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 821,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-OneSynthesized with (+) Acid

(A) (+)-5-(p-Chlorobenzoyl)-1,α-dimethylpyrrole-2-acetic acid

The mother liquors set aside in Example 81 are evaporated to dryness.The residue is acidified with 3N hydrochloric acid and the precipitatedacid is extracted into ether. The ether solution is then extracted withsaturated sodium bicarbonate solution. The latter is acidified withdilute HCl, and the precipitated solid is extracted into ether. Theether solution is washed with brine, dried over anhydrous magnesiumsulfate and evaporated to dryness to yield5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid [presumablyrich in the (+) enanthiomorph] as a yellow solid. A 14.8 g. sample isdissolved in ethanol. To the solution is added 6.15 g. (0.051 mole) of(-)-α-methylbenzylamine. A crystalline salt precipitates on standingwhich is collected and recrystallized three times from 2-propanol togive about 6.6 g. of white crystals, m.p. 175-177° C. The salt ispartitioned between ether and 3N HCl solution. The ether layer is washedwith dilute HCl and brine and dried over magnesium sulfate. The solventis partially evaporated in vacuo, and methylcyclohexane is added. Theether is allowed to evaporate at room temperature, and the precipitateis collected. It is recrystallized once more in the same manner to yield(21% yield) of (+)-5-(p-chlorobenzoyl)-1,α-dimethylpyrrole-2-acetic acidas a white solid, m.p. 105.5-106.5° C.

(B)1,6-Dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-pentalen-2-onesynthesized with (+) acid

The acid from Example 82A is subjected to the procedure of Example 1,part C to produce1,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-pentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-chlorophenyl, R₄ =methyl, R₅ =H, Y=CO, m=1,n=0).

EXAMPLE 834,6-Dimethyl-5-(4'-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) 3-Carboxy-1,4-dimethylpyrrole-2-acetic acid

A mixture of 176 g. (0.7 mole) of ethyl1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate and 1760 ml. of 25%sodium hydroxide solution is heated under reflux for 3 hours and thencooled and acidified with dilute hydrochloric acid. The precipitatedsolid is filtered and air dried. There is obtained3-carboxy-1,4-dimethylpyrrole-2-acetic acid as a gray solid, m.p.220-222° C.

(B) Ethyl 3-carboxy-1,4-dimethylpyrrole-2-acetate

A solution of 130 g. (0.66 mole) of3-carboxy-1,4-dimethylpyrrole-2-acetic acid in 1300 ml. of 0.5%ethanolic hydrogen chloride is heated under reflux for 45 minutes, andthen filtered while hot. A white solid, ethyl3-carboxy-1,4-dimethylpyrrole-2-acetate, precipitates from the filtrateon cooling, m.p. 182-185° C.

(C) Ethyl 1,4-dimethylpyrrole-2-acetate

A 70.0 g. sample (0.31 mole) of ethyl3-carboxy-1,4-dimethylpyrrole-2-acetate is heated under nitrogen at190-210° C. until gas evolution ceases. The resulting yellow liquid isdistilled at 82-90° C. at 0.25 mm. to give about 41 g. (73% yield) of aclear colorless liquid, ethyl 1,4-dimethylpyrrole-2-acetate.

(D) Ethyl 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate

A solution of 3.95 g. (0.025 mole) of p-fluorobenzoyl chloride and 3.32g. (0.025 mole) of aluminum chloride in 20 ml. of 1,2-dichloroethane isadded dropwise to a solution of 4.52 g. (0.025 mole) of ethyl1,4-dimethylpyrrole-2-acetate in 20 ml. of 1,2-dichloroethane at roomtemperature. The reaction mixture is stirred for 2 hours, and thencooled and poured into ice-dilute HCl. The organic phase is separatedand washed successively with N,N-dimethyl-1,3-propanediamine, dilutehydrochloric acid and a saturated solution of sodium chloride; driedover anhydrous magnesium sulfate; and the solvent evaporated. Theresidue is triturated with hot hexane and crystals form upon cooling.There is obtained about 1.9 g. (25% yield) of ethyl1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate as a white solid,m.p. 84-86° C. Upon recrystallization from methanol, the m.p. is 87-89°C.

(E) 1,4-Dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic acid

A suspension of 3.03 g. (0.01 mole) of ethyl1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate in 11 ml. of 1Nsodium hyroxide solution is heated under reflux for 30 minutes. Thesolution is filtered while hot and acidified with dilute hydrochloricacid. The precipitate is collected, air dried and recrystallized from2-propanol to give about 2.5 g. (91% yield) of1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic acid as a white solid,m.p. 176-178° C.

(F)4,6-Dimethyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-(p-fluorobenzoyl)-pyrolle-2-acetic acid is subjected tothe procedure of Example 1, part C to produce4,6-dimethyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-fluorophenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1,n=0).

EXAMPLE 844,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalene-2-One

(A) Ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of p-chlorobenzoyl-chloride is substitutedfor the p-fluorobenzoyl chloride used therein to yield ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate, m.p. 107-109° C.

(B) 1,4-Dimethyl-5-(p-chlorobenzoyl)pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(p-chlorobenzoyl)pyrrole-2-acetic acid.

(C)4,6-Dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalene1,4-Dimethyl-5-(p-chlorobenzoyl)pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalene(R₁ =H, R₂ =H, R₃ =4'-Chlorophenyl, R₄ =Methyl, R₅ =Methyl, Y=CO, m=1,n=0).

EXAMPLE 854,6-Dimethyl-5-(4'-Nitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of p-nitrobenzoyl chloride is substitutedfor the p-fluorobenzoyl chloride used therein to yield ethyl5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate.

(B) 1,4-Dimethyl-5-(p-nitrobenzoyl)pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(p-nitrobenzoyl)pyrrole-2-acetic acid.

(C)4,6-Dimethyl-5-(4'-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-(p-nitrobenzoyl)pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce4,6-dimethyl-5-(4'-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-nitrophenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1,n=0).

EXAMPLE 864,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of benzoylchloride is substituted for thep-fluorobenzoyl chloride used therein to yield ethyl5-benzoyl-1,4-dimethylpyrrole-2-acetate, m.p. 78-80° C.

(B) 1,4-Dimethyl-5-benzoyl-pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-benzoyl-pyrrole-2-acetic acid.

(C) 4,6-Dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-benzoyl-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁ =H,R₂ =H, R₃ =phenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 874,6-Dimethyl-5-(2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of 2'-thenoylchloride is substituted for thep-fluorobenzoyl chloride used therein to yield ethyl5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate.

(B) 1,4-Dimethyl-5-(2'-thenoyl)-pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(2'-thenoyl)-pyrrole-2-acetic acid.

(C) 4,6-Dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-(2'-thenoyl)-pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R₁=H, R₂ =H, R₃ =2'-thiophenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 884,6-Dimethyl-5-(5'-Methyl-2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of 5'-methyl-2'-thenoyl chloride issubstituted for the p-fluorobenzoyl chloride used therein to yield ethyl5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate.

(B) 1,4-Dimethyl-5-(5'-methyl-2'-thenoyl)pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(5'-methyl-2'-thenoyl)pyrrole-2-acetic acid.

(C)4,6-Dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-(5'-methyl-2'-thenoyl)pyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to produce4,6-dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =5'-methyl-2'-thiophenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 894,6-Dimethyl-5-(4'-Trifluoromethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of 4'-trifluoromethylbenzoyl chloride issubstituted for the p-fluorobenzoyl chloride used therein to yield ethyl5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate.

(B) 1,4-Dimethyl-5-(p-trifluoromethylbenzoyl)pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(p-trifluoromethylbenzoyl)pyrrole-2-acetic acid.

(C)4,6-Dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-(p-trifluoromethylbenzoyl)pyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to produce4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-trifluoromethylphenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 904,6-Dimethyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of 3',4'-dimethoxybenzoyl chloride issubstituted for the p-fluorobenzoyl chloride used therein to yield ethyl5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate.

(B) 1,4-Dimethyl-5-(3',4'-dimethoxybenzoyl)-pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(3',4'-dimethoxybenzoyl)-pyrrole-2-acetic acid.

(C)4,6-Dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-(3',4'-dimethoxybenzoyl)-pyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to produce4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =3',4'-dimethoxyphenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 914,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of 2',3',5'-tribromobenzoyl chloride issubstituted for the p-fluorobenzoyl chloride used therein to yield ethyl5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate.

(B) 1,4-Dimethyl-5-(2',3',5'-Tribromobenzoyl)pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(2',3',5'-tribromobenzoyl)pyrrole-2-acetic acid.

(C)4,6-Dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-(2',3',5'-tribromobenzoyl)pyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to produce4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =2',3',5'-tribromophenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 924,6-Dimethyl-5-(2'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of 2'-methylbenzoyl chloride is substitutedfor the p-fluorobenzoyl chloride used therein to yield ethyl5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate.

(B) 1,4-Dimethyl-5-(o-methylbenzoyl)pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(o-methylbenzoyl)pyrrole-2-acetic acid.

(C)4,6-Dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4-Dimethyl-5-(o-methylbenzoyl)pyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to produce4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =2'-methylphenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1,n=0).

EXAMPLE 934,6-Dimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate

The Friedel-Crafts acylation procedure of Example 83D is followed exceptthat an equivalent quantity of 4'-cyanobenzoyl chloride is substitutedfor the p-fluorobenzoyl chloride used therein to yield ethyl5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate.

(B) 1,4-Dimethyl-5-(p-cyanobenzoyl)pyrrole-2-acetic acid

The ester of part A of this Example is hydrolyzed in accordance with theprocedure of Example 83E to yield1,4-dimethyl-5-(p-cyanobenzoyl)pyrrole-2-acetic acid.

(C)4,6-Dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one1,4-Dimethyl-5-(p-cyanobenzoyl)pyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to produce4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =H, R₂ =H, R₃ =4'-cyanophenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1,n=0).

EXAMPLE 944,6-Dimethyl-5-(4'-Aminobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

By using an equivalent amount of4,6-dimethyl-5-(4'-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-onein place of 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetonitrile in thehydrogenation procedure of Example 85C, the product,4,6-dimethyl-5-(4'-aminobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-oneis obtained. (R₁ =H, R₂ =H, R₃ =4'-aminophenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 95Rac-1,4,6-Trimethyl-5-(4'-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 1,4,α-trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate (from Example 83) ismethylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl 1,4,α-trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate.

(B) 1,4,α-Trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into1,4,α-trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

1,4,α-Trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-fluorophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 96Rac-1,4,6-Trimethyl-5-(3'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(m-chlorobenzoyl)-1,4,cc-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl5-(m-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 84) ismethylated instead of the ethyl5-(m-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl 5-(m-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-(m-Chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(m-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(3'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(m-Chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(3'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =3'-chlorophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 97Rac-1,4,6-Trimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-benzoyl-1,4,α-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate(from Example 86) is methylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl 5-benzoyl-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-Benzoyl-1,4,α-trimethylpyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-benzoyl-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-Benzoyl-1,4,α-trimethylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to producerac-1,4,6-trimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =phenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1, n=0).

EXAMPLE 98Rac-1,4,6-Trimethyl-5-(2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(2'-thenoyl)-1,4,α-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from Example 87) ismethylated instead of the ethyl5-(m-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl 5-(2'-thenoyl)-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-(2'-Thenoyl)-1,4,α-trimethylpyrrole-2-acctic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(2'-thenoyl)-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2'-Thenoyl)-1,4,α-trimethylpyrrole-2-acetic acid is subjected to theprocedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =2'-thiophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 99Rac-1,4,6-Trimethyl-5-(5'-Methyl-2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(5'-methyl-2'-thenoyl)-1,4,α-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from Example 88)is methylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl5-(5'-methyl-2'-thenoyl)-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-(5'-Methyl-2'-thenoyl)-1,4,α-trimethylpyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Examples into5-(5'-methyl-2'-thenoyl)-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(5'-methyl-2'-thenoyl)-1,4,α-trimethylpyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =5'-methyl-2'-thiophenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 100Rac-1,4,6-Trimethyl-5-(4'-Trifluoromethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-trifluoromethylbenzoyl)-1,4,α-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example89) is methylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl5-(p-trifluoromethylbenzoyl)-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-(p-Trifluoromethylbenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-trifluoromethylbenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Trifluoromethylbenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-trifluoromethylphenyl, R₄ =methyl, R₅=methyl, Y=CO, m=1, n=0).

EXAMPLE 101Rac-1,4,6-Trimethyl-5-(3'4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(3',4'-dimethoxybenzoyl)-1,4,α-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example90) is methylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl5-(3',4'-dimethoxybenzoyl)-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-(3',4'-Dimethoxybenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(3',4'-dimethoxybenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(3'4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(3',4'-Dimethoxybenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(3'4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =3',4'-dimethoxyphenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 102Rac-1,4,6-Trimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapcntalen-2-One

(A) Ethyl 5-(2',3',5'-tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example91) is methylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl5-(2',3',5'-tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-(2',3',5'-Tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(2',3',5'-tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2',3',5'-Tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid issubjected to the procedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =2',3',5'-tribromophenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 103Rac-1,4,6-Trimethyl-5-(2'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(2'-methylbenzoyl)-1,4,α-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of ethyl5-(2'-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 92) ismethylated instead of the ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A,to yield ethyl 5-(2'-methylbenzoyl)-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-(2'-Methylbenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(2'-methylbenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2'-Methylbenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid is subjectedto the procedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =2'-methylphenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 104Rac-1,4,6-Trimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-cyanobenzoyl)-1,4,α-trimethylpyrrole-2-acetate

The methylation procedure of Example 77A is repeated, except that anequivalent quantity of (from Example 93) is methylated instead of theethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example77A, to yield ethyl 5-(p-cyanobenzoyl)-1,4,α-trimethylpyrrole-2-acetate.

(B) 5-(p-Cyanobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-cyanobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid.

(C)Rac-1,4,6-trimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Cyanobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid is subjected tothe procedure of Example 1, part C to producerac-1,4,6-trimethyl-5-(4'cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =methyl, R₂ =H, R₃ =4'-cyanophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 105Rac-1-(n-Propyl)-4,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 84),using an equivalent quantity of n-propyl iodide instead of methyl iodideused in Example 77A to yield ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)acetate.

(B) 5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-propyl)-acetic acid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-propyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =4'-chlorophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 106Rac-1-(n-Propyl)-4,6-Dimethyl-5-(4'-Nitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapcntalen-2-One

(A) Ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 85),using an equivalent quantity of n-propyl iodide instead of methyl iodideused in Example 77A to yield ethyl5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.

(B) 5-(p-Nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(4'-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(4'-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =4'-nitrophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 107Rac-1-(n-Propyl)-4,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-benzoyl-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-benzoyl-1,4-dimethylpyrrole-2-acetate (from Example 86), using anequivalent quantity of n-propyl iodide instead of methyl iodide used inExample 77A to yield ethyl5-benzoyl-1,4-dimethylpyrrole-2-α-n-propyl)-acetate.

(B) 5-Benzoyl-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-benzoyl-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-Benzoyl-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid is subjected tothe procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =phenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1,n=0).

EXAMPLE 108Rac-1-(n-Propyl)-4,6-Dimethyl-5-(2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from Example 87), using anequivalent quantity of n-propyl iodide instead of methyl iodide used inExample 77A to yield ethyl5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.

(B) 5-(2'-Thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2'-Thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =2'-thiophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 109Rac-1-(n-Propyl)-4,6-Dimethyl-5-(5'-Methyl-2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl5-(5'-methylthenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from Example88), using an equivalent quantity of n-propyl iodide instead of methyliodide used in Example 77A to yield ethyl5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.

(B) 5-(5'-Methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(5'-Methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acidis subjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =5'-methyl-2'-thiophenyl, R₄ =methyl, R₅=methyl, Y=CO, m=1, n=0).

EXAMPLE 110Rac-1-(n-Propyl)-4,6-Dimethyl-5-(4'-Trifluoromethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example89), using an equivalent quantity of n-propyl iodide instead of methyliodide used in Example 77A to yield ethyl5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.

(B)5-(p-Trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid is subjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, H, R₃ =4'-trifluoromethylphenyl, R₄ =methyl, R₅=methyl, Y=CO, m=1, n=0).

EXAMPLE 111Rac-1-(n-Propyl)-4,6-Dimethyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example90), using an equivalent quantity of n-propyl iodide instead of methyliodide used in Example 77A to yield ethyl5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.

(B) 5-(3',4'-Dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(3',4'-Dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid is subjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =3',4'-dimethoxyphenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 112Rac-1-(n-Propyl)-4,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example91), using an equivalent quantity of n-propyl iodide instead of methyliodide used in Example 77A to yield ethyl5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.

(B)5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-aceticacid is subjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =2',3',5'-tribromophenyl, R₄ =methyl, R₅=methyl, Y=CO, m=1, n=0).

EXAMPLE 113Rac-1-(n-Propyl)-4,6-Dimethyl-5-(2'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 92),using an equivalent quantity of n-propyl iodide instead of methyl iodideused in Example 77A to yield ethyl5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.

(B) 5-(o-Methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(o-Methylbenzoyl)-1,4-dimethylpyrrolc-2-(α-n-propyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =2'-methylphenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 114Rac-1-(n-Propyl)-4,6-Dimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 93),using an equivalent quantity of n-propyl iodide instead of methyl iodideused in Example 77A to yield ethyl5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.

(B) 5-(p-Cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid.

(C)Rac-1-(n-propyl)-4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-propyl)-4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-propyl, R₂ =H, R₃ =4'-cyanophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 115Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 84),using an equivalent quantity of n-hexyl iodide instead of methyl iodideused in Example 77A to yield ethyl5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)acetate.

(B) 5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid.

(C)Rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =4'-chlorophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 116Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(4'Nitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 85),using an equivalent quantity of n-hexyl iodide instead of methyl iodideused in Example 77A to yield ethyl5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B) 5-(p-Nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid.

(C) Rac-1-(n-hexyl)-4,6-dimethyl-5-(4'nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(4'nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =4'-nitrophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 117Rac-1-(n-Hexyl)-4,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-benzoyl-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-benzoyl-1,4-dimethylpyrrole-2-acetate (from Example 86), using anequivalent quantity of n-hexyl iodide instead of methyl iodide used inExample 77A to yield ethyl5-benzoyl-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B) 5-Benzoyl-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-benzoyl-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid.

(C)Rac-1-(n-hexyl)-4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-Benzoyl-1,4-dimethylpyrrole-2-α-n-hexyl)-acetic acid is subjected tothe procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =phenyl, R₄ =methyl, R₅ =methyl, Y=CO, m=1,n=0).

EXAMPLE 118Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from Example 87), using anequivalent quantity of n-hexyl iodide instead of methyl iodide used inExample 77A to yield ethyl5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B) 5-(2'-Thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid.

(C)Rac-1-(n-hexyl)-4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2'-Thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =2'-thiophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 119Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(5'-Methyl-2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(5'-methylthenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from Example88), using an equivalent quantity of n-hexyl iodide instead of methyliodide used in Example 77A to yield ethyl5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B) 5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-aceticacid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid.

(C)Rac-1-(n-hexyl)-4,6-dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(5'-Methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acidis subjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(5-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =5'-methyl-2'-thiophenyl, R₄ =methyl, R₅=methyl, Y=CO, m=1, n=0).

EXAMPLE 120Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(4'-Trifluoromethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example89), using an equivalent quantity of n-hexyl iodide instead of methyliodide used in Example 77A to yield ethyl5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B)5-(p-Trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-aceticacid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-aceticacid.

(C)Rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-aceticacid is subjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =4'-trifluoromethylphenyl, R₄ =methyl, R₅=methyl, Y=CO, m=1, n=0).

EXAMPLE 121Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example90), using an equivalent quantity of n-hexyl iodide instead of methyliodide used in Example 77A to yield ethyl5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B) 5-(3',4'-Dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-aceticacid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-aceticacid.

(C)Rac-1-(n-hexyl)-4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(3',4'-Dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acidis subjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =3',4'-dimethoxyphenyl, R₄ =methyl, R₅ =methyl,Y=CO, m=1, n=0).

EXAMPLE 122Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example91), using an equivalent quantity of n-hexyl iodide instead of methyliodide used in Example 77A to yield ethyl5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B)5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-aceticacid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-α-n-hexyl)-aceticacid.

(C) Rac-1-(n-hexyl)-4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-aceticacid is subjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =2',3',5'-tribromophenyl, R₄ =methyl, R₅=methyl, Y=CO, m=1, n=0).

EXAMPLE 123Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(2'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 92),using an equivalent quantity of n-hexyl iodide instead of methyl iodideused in Example 77A to yield ethyl5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B) 5-(o-Methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid.

(C)Rac-1-(n-hexyl)-4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(o-Methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =2'-methylphenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLE 124Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One

(A) Ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate

The alkylation procedure of Example 77A is performed upon ethyl5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetatc (from Example 93),using an equivalent quantity of n-hexyl iodide instead of methyl iodideused in Example 77A to yield ethyl5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.

(B) 5-(p-Cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid

The hydrolysis procedure of Example 77B is followed in transforming theester from part A of this Example into5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid.

(C)Rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one

5-(p-Cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetic acid issubjected to the procedure of Example 1, part C to producerac-1-(n-hexyl)-4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one(R₁ =n-hexyl, R₂ =H, R₃ =4'-cyanophenyl, R₄ =methyl, R₅ =methyl, Y=CO,m=1, n=0).

EXAMPLES 125-1364,6-Dialkyl-5-Aroyl-1,3,6-Trihydro-6-Aza-3-Oxa-Pentalen-2-One

(A) By repeating the procedure of Example 76B, except that an equivalentamount of ethylamine and n-butylamine is substituted for the methylamineemployed therein, there are obtained, as respective products, ethyl3-ethoxycarbonyl-1,4-diethylpyrrole-2-acetate and ethyl3-ethoxycarbonyl-1-n-butyl-4-ethylpyrrole-2-acetate.

(B) Similarly, by following the procedure of Example 76B, except that anequivalent amount of chloromethyl n-butyl ketone is substituted for the1-chloro-2-butanone used therein, ethyl3-ethoxycarbonyl-4-n-butyl-1-methylpyrrole-2-acetate is obtained.

(C) The procedure of Examples 83A through 83C are repeated, except thatan equivalent amount of each of the products obtained in paragraphs Aand B of this Example is substituted for the ethyl1,4-dimetyl-3-ethoxycarbonylpyrrole-2-acetate initially employed inExample 83A, to yield, as respective final products: ethyl1,4-diethylpyrrole-2-acetate; ethyl 1-n-butyl-4-ethylpyrrole-2-acetate;and ethyl 4-n-butyl-1-methylpyrrole-2-acetate.

(D) The Friedel-Crafts procedure of Example 83D is followed using anequivalent amount of the appropriate ester obtained in paragraph C ofthis Example and an equivalent amount of an appropriate Aryl chloride asthe acylating agent to yield the following products: ethyl5-(p-chlorobenzoyl)-1,4-diethylpyrrole-2-acetate; ethyl5-(2-thenoyl)-1,4-diethylpyrrole-2-acetate; ethyl5-(p-methylsulfonyl)-1-n-butyl-4-ethylpyrrole-2-acetate; ethyl5-(p-trifluoromethylbenzoyl)-1-n-butyl-4-ethylpyrrole-2-acetate; ethyl5-(p-nitrobenzoyl)-4-n-butyl-1-methylpyrrole-2-acetate; ethyl5-(p-cyanobenzoyl)-4-n-butyl-1-methylpyrrole-2-acetate; and ethyl5-(3',4'-dimethoxybenzoyl)-4-n-butyl-1-methylpyrrole-2-acetate.

(E) Each of the esters obtained in paragraph D of this Example ishydrolyzed in accordance with the procedure of Example 83E to yield thecorresponding 5-aryl derivatives of 1,4-dialkylpyrrole-2-acetic acid.

(F) 4,6-dialkyl-5-aroyl-1,3,6-trihydro-6-aza-3-oxa-pentalen-2-one

The acids from part E are subjected to the procedure of Example 1, partC to produce the corresponding4,6-dialkyl-5-aroyl-1,3,6-trihydro-6-aza-3-oxa-pentalen-2-ones (R₁ =H,R₂ =H, =H, R₃ =aryl, R₄ =alkyl, R₅ =alkyl, Y=CO, m=1, n=0).

We claim:
 1. A compound of the formula: ##STR5## wherein R₁ and R₂ areindependently selected from the group consisting of hydrogen, loweralkyl, and benzyl;R₃ is selected from the group consisting ofsubstituted or unsubstituted phenyl, pyrrolyl, pyrrolidinyl, furfuryl,and thiophenyl, wherein said substitutents are one to threeindependently selected from the group consisting of halogen, loweralkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino,hydroxy, nitro, nitrile, carboxyl, aminosulfonyl, lower alkyl mercapto,and lower alkylsulfonyl; R₄ is selected from the group consisting ofsubstituted or unsubstituted phenyl, pyrrolyl, pyrrolidinyl furfuryl,and thiophenyl; wherein said substitutents are one to threeindependently selected from the group consisting of halogen, loweralkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino,hydroxy, nitro, nitrile, carboxyl, aminosulfonyl, lower alkyl mercapto,and lower alkylsulfonyl; R₅ is selected from the group consisting ofhydrogen, lower alkyl, halogen, hydroxy, amino, lower alkyl amino, anddi-lower alkylamino; Y is selected from the group consisting of CH₂,C═O, CH--OH m is an integer from 0-3 X is selected from the groupconsisting of CH₂, C═O, CH--OH, and SO₂ ; and n is an integer from 0-2.2. The compound of claim 1 wherein R₁ and R₂ are independently selectedfrom the group consisting of hydrogen, and lower alkyl.
 3. The compoundof claim 2 wherein R₁ and R₂ are both hydrogen.
 4. The compound of claim3 wherein R₃ is selected from the group consisting of substituted orunsubstituted phenyl wherein said substitutents are one to threeindependently selected from the group consisting of lower alkyl, loweralkoxy, di-lower alkylamino, aminosulfonyl, and lower alkylsulfonyl. 5.The compound of claim 4 wherein R₅ is selected from the group consistingof hydrogen, lower alkyl, hydroxy, and di-lower alkylamino.
 6. Thecompound of claim 4 wherein R₅ is selected from the group consisting ofhydrogen and lower alkyl.
 7. The compound of claim 5 wherein Y isselected from the group consisting of C═O and CH--OH and m is an integerfrom 0-2.
 8. The compound of claim 6 wherein Y is C═O, and m is 0 or 1.9. The compound of claim 7 wherein X is selected from the groupconsisting of CH₂, C═O, and SO₂ ; and n is 0 or
 1. 10. A method oftreating a patient having neoplasia comprising administering apharmacologically effective amount of a compound of Formula I to thepatient with a neoplasia sensitive to such a compound: ##STR6## whereinR₁ and R₂ are independently selected from the group consisting ofhydrogen, lower alkyl, and benzyl;R₃ is selected from the groupconsisting of substituted or unsubstituted phenyl, pyrrolyl,pyrrolidinyl, furfuryl, and thiophenyl, wherein said substitutents areone to three independently selected from the group consisting ofhalogen, lower alkyl, lower alkoxy, amino, lower alkylamino, di-loweralkylamino, hydroxy, nitro, nitrile, carboxyl, aminosulfonyl, loweralkyl mercapto, and lower alkylsulfonyl; R₄ is selected from the groupconsisting of substituted or unsubstituted phenyl, pyrroyl, pyrrolidinylfurfuryl, and thiophenyl; wherein said substitutents are one to threeindependently selected from the group consisting of halogen, loweralkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino,hydroxy, nitro, nitrile, carboxyl, aminosulfonyl, lower alkyl mercapto,and lower alkylsulfonyl; R₅ is selected from the group consisting ofhydrogen, lower alkyl, halogen, haydroxy, amino, lower alkyl amino, anddilower alkylamino; Y is selected from the group consisting of CH₂, C═O,CH--OH m is an integer from 0-3 X is selected from the group consistingof CH₂, C═O, CH--OH, and SO₂ ; and n is an integer from 0-2.
 11. Themethod of claim 10 wherein R₁ and R₂ are independently selected from thegroup consisting of hydrogen, and lower alkyl.
 12. The method of claim11 wherein R₁ and R₂ are both hydrogen.
 13. The method of claim 12wherein R₃ is selected from the group consisting of substituted orunsubstituted phenyl wherein said substitutents are one to threeindependently selected from the group consisting of lower alkyl, loweralkoxy, di-lower alkylamino, aminosulfonyl, and lower alkylsulfonyl. 14.The method of claim 13 wherein R₅ is selected from the group consistingof hydrogen, lower alkyl, hydroxy, and di-lower alkylamino.
 15. Themethod of claim 13 wherein R₅ is selected from the group consisting ofhydrogen and lower alkyl.
 16. The method of claim 14 wherein Y isselected from the group consisting of C═O and CH--OH and m is an integerfrom 0-2.
 17. The method of claim 15 wherein Y is C═O, and m is 0 or 1.18. The method of claim 16 wherein X is selected from the groupconsisting of CH₂, C═O, and SO₂ ; and n is 0 or 1.